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Review

The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma

by
Justus Lieber
*,
Sorin Armeanu-Ebinger
and
Jörg Fuchs
Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Hoppe-Seyler-Strasse 1, Tübingen D-72076, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2015, 16(2), 4190-4208; https://doi.org/10.3390/ijms16024190
Submission received: 29 November 2014 / Revised: 1 February 2015 / Accepted: 9 February 2015 / Published: 16 February 2015
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)
Browse Figure
Figure 1
<p>Effects of BH3-mimetic drugs. Overexpression of proteins of the Bcl-family in tumor cells cause capture of Bak and Bax in BH3-binding sites, which prevents initiation of the apoptosis cascade via intrinsic or extrinsic stimuli (<b>A</b>); BH3-mimetic drugs lead to the release of Bak and Bax, which oligomerize and insert as a complex in the outer mitochondrial membrane. This membrane permeabilisation is followed by cytochrome c release and other pro-apoptotic factors into the cytoplasm, initiating apoptosis and leading to cell death (<b>B</b>); BH3-mimetic drugs can enhance dead signals from immune cells (TRAIL, TNF-α) and can influence migration of tumor cells (<b>C</b>).</p> ">
Versions Notes

Abstract

:
Pediatric hepatoblastoma (HB) is commonly treated by neoadjuvant chemotherapy and surgical tumor resection according to international multicenter trial protocols. Complete tumor resection is essential and survival rates up to 95% have now been achieved in those tumors classified as standard-risk HB. Drug resistance and occurrence of metastases remain the major challenges in the treatment of HB, especially in high-risk tumors. These conditions urgently require the development of alternative therapeutic strategies. One of those alternatives is the modulation of apoptosis in HB cells. HBs regularly overexpress anti-apoptotic proteins of the Bcl-family in comparison to healthy liver tissue. This fact may contribute to the development of chemoresistance of HB cells. Synthetic small inhibitory molecules with BH3-mimetic effects, such as ABT-737 and obatoclax, enhance the susceptibility of tumor cells to different cytotoxic drugs and thereby affect initiator proteins of the apoptosis cascade via the intrinsic pathway. Besides additive effects on HB cell viability when used in combination with cytotoxic drugs, BH3-mimetics also play a role in preventing metastasation by reducing adhesion and inhibiting cell migration abilities. Presumably, including additive BH3-mimetic drugs into existing therapeutic regimens in HB patients might allow dose reduction of established cytotoxic drugs and thereby associated immanent side effects, while maintaining the antitumor activity. Furthermore, reduction of tumor growth and inhibition of tumor cell dissemination may facilitate complete surgical tumor resection, which is mandatory in this tumor type resulting in improved survival rates in high-risk HB. Currently, there are phase I and phase II clinical trials in several cancer entities using this potential target. This paper reviews the available literature regarding the use of BH3-mimetic drugs as single agents or in combination with chemotherapy in various malignancies and focuses on results in HB cells.

1. Introduction

Hepatoblastoma (HB) is the most common primary malignant pediatric liver tumor in children with an incidence of 1.2 per million and an overall median age at diagnosis of 18 months [1]. Histologically, the tumors are divided into epithelial and mixed epithelial/mesenchymal subtypes. Tumor cells may appear with a wide variety of characteristics ranging from almost liver-cell-like to undifferentiated blastomal cells. The majority of HB is epithelial, consisting of embryonal and fetal cells. About 5% of the tumors belong to the small-cell undifferentiated subtype, which is associated with a worse prognosis [2]. HB usually expresses α-fetoprotein (AFP), which is also elevated in the serum of 90% of children with this tumor. AFP serves as a tumor marker, as an indicator for treatment response, and as a follow up marker to detect early relapses. For laboratory experiments, the HB cell lines HepT1 (derived from a multifocal embryonal HB [3]) and HuH6 (derived from a mixed HB with focal chondroosteogenic tissue and a squamous cell morphology [4]) were eligible.

2. Established Treatment Strategies against HB

To date, treatment strategies against HB have been established, constantly evaluated, and revised by cooperative study groups (Childhood Liver Tumor Strategy Group (SIOPEL), the Children’s Oncology Group (COG), and the national study groups from Germany (GPOH) and Japan (JPLT)) [5,6]. The main goal of treatment is complete surgical resection of the tumor, because this is essential for survival of the patient [7,8]. However, surgery alone can cure very few patients with HB, because more than half of them present with unresectable primary tumors or distant metastases. Evidence that HB is a chemosensitive tumor has led to a combined treatment regiment consisting of surgery and chemotherapy [9]. Neoadjuvant chemotherapy usually leads to tumor shrinkage and makes the tumor more solid, less prone to bleeding and more demarcated from the remaining healthy liver parenchyma, which consequently leads to increased rates of complete tumor resection [10]. Also, potentially existing micrometastases in the lungs are treated early. The exact treatment protocol depends on the tumor stage. Currently, staging of tumors is usually performed according to the PRETEXT (Pretreatment Extent of Disease) system, which is based on pretreatment imaging using ultrasound, computed tomography (CT) scans and/or magnetic resonance imaging (MRI) [11]. It describes the site and size of the tumor, vascular invasion, and distant spread. The staging system identifies four PRETEXT stages (I–IV), which reflect the number of sections of the liver that are involved by the tumor and describes the extent of the disease beyond the liver using letters as mentioned in Table 1. In principle, HB tumors are stratified into risk groups, which differ slightly between the different international study groups.
Table
Table 1. International risk stratification [12]. Risk stratification of children with Hepatoblastoma (HB) reflecting the respective international treatment protocols, COG: Children’s Oncology Group; SIOPEL: International Childhood Liver Tumour Strategy Group; JPLT: Japanese Pediatric Liver Tumour Study Group; GPOH: German Society of Pediatric Oncology and Hematology; SCU: small cell undifferentiated; AFP: α-fetoprotein, V (tumor extends into the vena cava and/or all three hepatic veins), P (the main and/or both left and right branch/es of the portal vein are involved by the tumor), E (evidence of extrahepatic intra-abdominal disease), and M (distant metastases).
Table 1. International risk stratification [12]. Risk stratification of children with Hepatoblastoma (HB) reflecting the respective international treatment protocols, COG: Children’s Oncology Group; SIOPEL: International Childhood Liver Tumour Strategy Group; JPLT: Japanese Pediatric Liver Tumour Study Group; GPOH: German Society of Pediatric Oncology and Hematology; SCU: small cell undifferentiated; AFP: α-fetoprotein, V (tumor extends into the vena cava and/or all three hepatic veins), P (the main and/or both left and right branch/es of the portal vein are involved by the tumor), E (evidence of extrahepatic intra-abdominal disease), and M (distant metastases).
Risk GroupCOGSIOPELJPLTGPOH
Very low riskPRETEXT I or II, pure fetal histology and primary resection–––
Low risk/ Standard riskPRETEXT I or II, any histology primary resectionPRETEXT I, II, IIIPRETEXT I, II, IIIPRETEXT I, II, III
Intermediate riskPRETEXT II, III, IV unresectable at diagnosis V+, P+, E+ SCU–PRETEXT IV, any tumor with rupture, N1,P2,P2a,V3, And V3a multifocal–
High riskAny PRETEXT, M+, AFP < 100ng/mLAny PRETEXT, V+, P+, E+, M+, SCU, AFP < 100 ng/mL, tumor ruptureAny PRETEXT, M1, N2, AFP < 100 ng/mLAny PRETEXT, V+, P+, E+, M+, multifocal
Standard-risk (SR)-HB are defined as PRETEXT stage I, II or III tumors without metastases, vascular involvement or extrahepatic disease. High-risk (HR)-HBs are PRETEXT stage IV tumors and/or one or more of the following criteria are present: Extrahepatic diseases (usually lung metastases), low AFP-values (<100 ng/mL), and/or tumor rupture [13].
The use of chemotherapy is uncontroversial in HB and it is applied according to the risk groups. Most SR-HB show a good response to chemotherapy, in which cisplatin has proven to be sufficient even applied as monotherapy [14]. Historically, combinations of cytotoxic drugs were use, such as cisplatin and doxorubicin (SIOPEL-3SR), or additional ifosfamid (German HB-99 study), but results were not superior to cisplatin monotherapy. On the contrary, intensity of monochemotherapy with cisplatin could be reduced while maintaining good treatment results [6,15]. For HR-HB, strategies were developed comprising intensification and/or combination of cytostatic chemotherapeutics, such as cisplatin, doxorubicin, vincristine, fluorouracil, carboplatin, ifosfamide, etoposide, and others in the North American, German, and Japanese trials [5,16,17,18,19,20]. However, the prognosis of patients with tumors involving all four liver sections or with distant metastases still remains unsatisfactory. For example in the SIOPEL trials, the 5-year event-free survival (EFS) in these patients after preoperative PLADO (cisplatin and doxorubicin) and delayed surgery (SIOPEL-1) was 46% (PRETEXT-IV), or 28% (metastases), respectively [21]. In a pilot study (SIOPEL-2HR) and the following SIOPEL-3HR trial, carboplatin was added to the PLADO backbone and led to improved survival in patients with PRETEXT-IV tumors (3-year EFS 68%) or metastases (56%) [15]. SIOPEL-4 aimed to further intensify chemotherapy in HR-HB by adopting a dense weekly dose administration of cisplatin in combination with monthly doxorubicin and delayed radical surgery [22]. Complete resection was achieved in 85% of patients including liver transplants and the 3-years EFS rate was 76%.
Even though optimization and intensification of chemotherapy leads to improved treatment results, it cannot eradicate primary tumors alone [6,16]. Surgical strategies for tumor resection include anatomic liver resections and liver transplantation [23,24]. Atypical, nonanatomic, or wedge resections are associated with a worse outcome, for which the presence of unappreciated microscopic vascular invasion and the known role of hepatocyte growth factor (HGF) in stimulating post-resection liver regeneration and residual tumor cell proliferation might be possible explanations [16,25]. Anatomic liver resection is recommended as lobectomy or segmentectomy at diagnosis for PRETEXT I, as lobectomy or trisegmentectomy after neoadjuvant chemotherapy for PRETEXT II and III, and as liver transplant or extreme resection for any PRETEXT IV. Although primary liver transplantation has excellent results, there is an ongoing discussion regarding the optimal procedure for tumors that are very large or critically positioned and impinge on essential vascular structures, and for tumors that are multicentric and present in all four sectors of the liver before neoadjuvant therapy. However, rescue transplantation (transplantation after initial liver resection) is not as effective as primary liver transplantation.

3. Specific Treatment Strategies against HB

Even though standard treatment protocols for HB have constantly been optimized, unsatisfactory results are still observed in some patients, especially in those with HR-HB. The main reasons for poor outcome is chemoresistance, unresectability of tumors or recurrence of disease. Therefore, various alternative treatment options have been proposed (Table 2).
Table
Table 2. Selective alternative treatment proposals for HR-HB.
Table 2. Selective alternative treatment proposals for HR-HB.
OptionSubstancePathwayReference
Gene-directed therapy with prodrugs5-fluorocytosineConverting non-toxic drugs into antiproliferative drugs[26]
Kinase inhibitorssorafenib, rapamycin–[27,28]
Control of gene expressionEpigenetic modulatorsDNA methylation and histone acetylation[29]
Protein homeostasisProteasome inhibitorsDegradation of proteins[30]
Modulation of apoptosisTNF-α, TRAILInduction of apoptosis, signal transduction[31]
–Downregulation of Bcl-2 using siRNA[32]
ToxificationHigh dose acetaminophen with N-acetylcysteine–[33]
ImmunotherapyAllogeneic graft-versus-HB effect.Hematopoietic stem cell transplantation[34]
Natural killer cell-mediated lysis of hepatoma cellsAntitumor immune responses[35,36]
Oncolytic virotherapyModified Adeno and Sendai virusesCancer-specific replication of viruses[37,38]

4. Resistance Mechanisms in HB Cells

A major challenge for cancer treatment remains the development of drug resistance, a mechanism by which tumor cells achieve insensitivity to external insult or internal damage. Most HBs are generally chemosensitive; however, 80% of HBs develop drug resistance after four cycles of chemotherapy [39]. Several mechanisms in cancer cells to evade death signals have been identified contributing to multi-drug-resistance (MDR). Reports exist in this regard on overexpression of MDR-associated genes (e.g., P-glycoprotein), increased DNA repair, alternations in target molecules (e.g., topoisomerasis II), overexpression of detoxifying enzymes (e.g., Glutathion-S-Transferase), and others [40,41,42,43]. MDR is also caused by gene deletion or mutation (e.g., p. 53 [44]), which leads to deregulation of apoptosis.
Apoptosis is an orchestrated cellular process important for maintaining homeostasis between cell proliferation and cell death, including the removal of diseased or damaged cells [45]. Apoptosis can be induced in two distinct pathways, both of which lead to the activation of effector caspases. The intrinsic pathway is substantially regulated by proteins of the B-cell lymphoma-2 (Bcl-2) family. Bcl-2 proteins share one of four Bcl-2 homology (BH1-4) domains, of which the BH3-domain is critical for mediating interactions among the family members [46]. Bcl-2 proteins can be grouped as anti-apoptotic (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and Bfl-1/A1) and pro-apoptotic. The latter group can be further divided as either multi-BH-domain proteins, including Bax and Bak, or as BH3-only proteins, such as Bid, Bad, Bim, Puma, and Noxa [47,48,49]. The BH3-domain is—in the presence of Bax and Bak—essential for the death function of BH3-only proteins [50]. Death signals caused by DNA-damage, deprivation of growth factors or activation of oncogenes lead to transcriptional or posttranslational modification of BH3-only proteins [49,51]. Consequently, Bak and Bax oligomerize and insert as complex in the outer mitochondrial membrane [50,52,53]. This membrane permeabilisation (MOMP = mitochondrial outer membrane permeabilization) is followed by cytochrome c release and other pro-apoptotic factors into the cytoplasm, initiating the apoptosis cascade and leading to cell death (Figure 1).
Ijms 16 04190 g001 1024
Figure 1. Effects of BH3-mimetic drugs. Overexpression of proteins of the Bcl-family in tumor cells cause capture of Bak and Bax in BH3-binding sites, which prevents initiation of the apoptosis cascade via intrinsic or extrinsic stimuli (A); BH3-mimetic drugs lead to the release of Bak and Bax, which oligomerize and insert as a complex in the outer mitochondrial membrane. This membrane permeabilisation is followed by cytochrome c release and other pro-apoptotic factors into the cytoplasm, initiating apoptosis and leading to cell death (B); BH3-mimetic drugs can enhance dead signals from immune cells (TRAIL, TNF-α) and can influence migration of tumor cells (C).
Figure 1. Effects of BH3-mimetic drugs. Overexpression of proteins of the Bcl-family in tumor cells cause capture of Bak and Bax in BH3-binding sites, which prevents initiation of the apoptosis cascade via intrinsic or extrinsic stimuli (A); BH3-mimetic drugs lead to the release of Bak and Bax, which oligomerize and insert as a complex in the outer mitochondrial membrane. This membrane permeabilisation is followed by cytochrome c release and other pro-apoptotic factors into the cytoplasm, initiating apoptosis and leading to cell death (B); BH3-mimetic drugs can enhance dead signals from immune cells (TRAIL, TNF-α) and can influence migration of tumor cells (C).
Ijms 16 04190 g001
MOMP is regarded as one key element in the initiation of the apoptosis cascade [46]. A carefully regulated balance between pro-apoptotic and anti-apoptotic members of the Bcl-2 family determines the survival of the cell [54,55].
The extrinsic pathway of apoptosis is initiated on the plasma membrane upon ligation of death receptors and can be promoted by immune cells such as natural killer (NK) cells, T cells, and liver-specific Kupffer cells. These cells secrete proteins of the TNF (tumor necrosis factor) family such as TNF-α, FasL, and TRAIL (tumor necrosis factor-related apoptosis inducing ligand). Receptor binding recruits pro-caspase 8 into the death-inducing silencing complex. Cleavage of the BH3-only peptide, Bid, by caspase 8 links the apoptotic TRAIL signal to the mitochondrial pathway and the subsequent release of cytochrome c [56].
Overexpression of anti-apoptotic proteins or loss of pro-apoptotic members of the Bcl-2 family as well as a lost ability to express death receptors render cells correspondingly susceptible or resistant to apoptosis [57]. This mechanism is believed to contribute to tumor initiation and progression as well as to treatment resistance in various cancer types (colon, endometrial, Burkitt’s lymphoma, and ovary) [56,58,59]. Comparison of gene expression profiles of tumor samples with fetal liver tissue revealed downregulation of pro-apoptotic genes in HB samples as well, whereas a number of anti-apoptotic and prosurvival genes were upregulated [60,61]. In addition, TRAIL insensitivity has been described in HB cells, despite their expression of death receptors [62]. Therefore, modulation of apoptosis constitutes a promising therapeutic option for HB as it may resensitize tumor cells as targets of chemotherapeutic agents, mostly through induction of apoptosis.

5. Modulation of Apoptosis as a Concept of Anti-Tumor Therapy

The initial strategy of pharmacological inhibition of proteins of the Bcl-2 family was to use antisense oligonucleotides to inhibit transcription of mRNA in Bcl-2 [63]. Numerous other compounds with anti-cancer activity (e.g., epigallocatenin-3-gallate or chelerythrine) have been shown to antagonize the Bcl-2 family proteins. However, the clinical effect was only moderate [64,65]. Consequently, antagonization of function rather than reduction of proteins had been favored and small-molecule-inhibitors selective for anti-apoptotic Bcl-2 proteins have been identified [66,67]. Advances in crystallizing the Bcl-xL structure containing hydrophobic binding sites BH1–BH3, which usually bind to the α-helix of BH3-only proteins, has enabled the identification and synthesis of such small-molecular antagonists. They are in a competitive relationship with anti-apoptotic proteins and prevent the sequestration of pro-apoptotic BH3-only proteins such as tBid, Bad, Bax, and Bim [68]. Numerous natural organic compounds were found with BH3-mimetic effects of a broad affinity and specificity to Bcl proteins [46]. Currently, four Bcl-2 inhibitors are undergoing clinical trials: ABT-263 (navitoclax, an orally bioavailable analogue of ABT-737 [69], AT-101 [(−)-gossypol] [70], obatoclax (GX15-070) [71], and ABT-199 [72,73].

6. BH3-Mimetic Drugs as Sensitizers of Chemotherapy in HB

Small synthetic molecules with BH3-mimetic effects have been shown to enhance the intrinsic apoptotic pathway in several tumor cell lines. ABT-737 as single agent has shown moderate activity against several hematopoietic cell lines (leukemias, multiple myeloma, and cultured lymphoma) and some solid tumor cell lines, including prostate cancer, ovarian cancer, glioblastoma, and retinoblastoma. A high efficiency of single ABT-737 was only observed in small cell lung carcinoma [63,69,74,75,76,77,78,79,80]. In a xenograft model the highest efficiency of ABT-737 and a related compound, ABT-263, was observed when the IC50 in vitro was in a nanomolar range. Synergistic effects have been described with dexamethasone and melphalan in multiple myeloma and with cytotoxic drugs (e.g., paclitaxel, cisplatin, etoposide, doxorubicin) in a variety of tumor cell lines [67,81]. Obatoclax has also been shown to potentiate other cancer treatment approaches in xenograft models of small cell lung cancer, thyroid cancer, and colorectal cancer [70,82,83].
In HB cells, ABT-737 was found to induce apoptosis as a pan-Bcl-2 inhibitor at concentrations above 1 µM, whereas obatoclax similarly antagonized all anti-apoptotic Bcl-2 family proteins, including the dominant proteins Mcl-1 and Bfl-1, showing anti-apoptotic effects at a concentration as low as 0.03 µM [65,84]. Inhibition of these proteins using ABT-737 or obatoclax has induced significant reduction of HB cell proliferation [61,85]. It has also been demonstrated that these modulators of apoptosis enhance the effects of cytotoxic drugs in vitro and in vivo, where reduced proliferation rates were documented after combined treatment with ABT-737 and paclitaxel or cisplatin and reduction of tumor growth in a subcutaneous model of HB [86,87]. Other small molecular drugs with BH3-mimetic effect tested on HB cells, such as HA14-1 or TW37, did not show any significant effect as single agents, or in combination with several cytotoxic drugs [85].
ABT-737 inhibits the prosurvival function of Bcl-2, Bcl-xL, and Bcl-w, but exhibits low affinity to the anti-apoptotic Mcl-1 and A1 proteins. This anti-apoptotic group of Bcl-2 family proteins is frequently found to be overexpressed in numerous cancers including HB. Mcl-1 is expressed at high levels in HB, which are however inferior to expression levels in hepatocytes. This fact represents a relevant constraint for the efficiency of ABT-737. HB cells also express pro-apoptotic Bak, which has been described as key molecule for sensitizing tumor cells to ABT-737 [88,89]. However, the single-agent activity of ABT-737 is poor below doses of 1 mM. On the other hand it significantly potentiates the efficacy of established chemotherapeutic drugs on HB cells. Obatoclax has shown dose-dependent single-agent activity against HB cells at concentrations above 0.3 mM. Mechanistically, apoptosis induction by obatoclax can be preceded by liberation of Bak from Mcl-1, dissociation of Bim from Bcl-2, and Mcl-1 [90]. The additional binding on Mcl-1 proteins may enhance efficiency of obatoclax; however, gene expression analysis revealed a two-fold lower expression of Mcl-1 in native HB tissue and HuH6 cells than in normal liver tissue and a benefit of obatoclax was not expected [91,92]. On the other side, it has been proposed that obatoclax abolishes cell growth independently of apoptosis by inducing a S–G2 cell cycle block suggesting multiple targets of this agent [77]. These Bcl-2 independent targets of obatoclax may have clinical applicability, but mechanisms of these anti-proliferative effects on HB cells in particular require further investigations.
ABT-737 and obatoclax also enhance cytotoxic effects when combined with cisplatin, doxorubicin, etoposide, and paclitaxel, which are commonly used in treatment protocols of HB [6,93]. Cisplatin is the most important cytotoxic drug in the treatment of HB, and leads to an excellent 3-year survival rate of 96% in SR-HB, even when applied as monotherapy [14,21]. Therapy has been intensified in HR-HB using cisplatin monotherapy and second-line cytostatic drugs. However, significant irreversible adverse effects have been observed, such as nephro- and neurotoxicity as well as myelodepression or heart failure. Therefore, BH3-mimetic substances seem promising since they might enable dose reduction of cytotoxic drugs while maintaining their antitumor activity.
In general, the effects of ABT-737 and obatoclax were more relevant in HuH6 cells than in HepT1 cells. Higher concentrations of ABT-737 and obatoclax were used in HepT1 cells, but viability was reduced in HuH6 only. This enhanced sensibility of HuH6 cells does not correlate with the relative expression of anti- and pro-apoptotic proteins, as Bcl-xL, Bax, and Mcl-1 are similarly expressed in both cell lines. Therefore, we assume that a higher proliferation rate in HuH6 cells may explain the higher sensibility.
HA14-1 is an organic compound originally discovered by computer modeling. It is the first small molecule, which was predicted to bind to Bcl-2 with inhibitory effects [94]. HA14-1 has been shown to induce apoptosis in various hematopoietic and solid tumor cell lines, such as leukemias, lymphomas, breast and ovarian carcinomas, malignant glioma, multiple myeloma, and neuroblastoma [71,83,95,96,97,98]. A synergism with a variety of anti-cancer agents has also been described [99,100]. In HB cells no pro-apoptotic effects could be observed with HA14-1. A variable response ranging from partial to massive cell death has been described in other cell lines and it is known, that expression of HA14-1 targets (Bcl-2 and Bcl-xL) did not correlate to these different responses; consequently, the potentiating effect of HA14-1 might be drug- and cell-type specific [75]. HA14-1 is also highly unstable and may rapidly decompose to inactive compounds. Decomposition generates reactive oxygen species (ROS) resulting in potent pro-apoptotic activity, which makes interpretation of results in addition to effects of antagonizing anti-apoptotic Bcl-2 family proteins difficult [101,102]. In summary, HA14-1 did not show effects on HB cells in general and did not enhance effects when combined with cytotoxic drugs [85].
The anti-tumor action of TW-37; which also binds to the BH3 groove of Bcl-2; is assumed to be due to a combination of a pro-apoptotic and specific anti-angiogenic effects as described in head and neck small cell carcinoma; pancreatic cancer; and lymphoma cells. This effect has been observed as single agent and in combination with cytotoxic drugs [76,103]. In HB cells; effects of TW-37 were moderate. Surprisingly; no additive effects after combination with cisplatin or other tested cytotoxic drugs were seen; as reported for head and neck squamous cell carcinomas (HNSCC); for which cisplatin is also commonly used in current treatment protocols [104]. Both; HNSCC and HB; express high levels of Bcl-2; so that the mechanism for the absence of additive effects in HB cells remains unclear. The IC50 for cisplatin in HuH6 and HNSCC (UM-SCC-1; UM-SCC-74A) was comparable; but required doses of TW-37 to significantly enhance effects of the combined treatment were three-fold lower in HNSCC.

7. BH3-Mimetic Drugs as Sensitizers of the Immune System in HB

The extrinsic pathway of apoptosis can be promoted by various immune cells that express proteins of the TNF family, such as TRAIL and/or TNF-α [105]. Thus, clinical trials in cancer patients have utilized soluble recombinant TRAIL and agonistic monoclonal antibodies that target TRAIL receptors as well as TNF-α. However, its clinical use is limited by severe dose-limiting toxicity [31,106]. In addition, liver tumors exhibit a variety of TRAIL and TNF-α resistance mechanisms, which emphasizes the necessity of a mechanism to restore the sensitivity of the tumor cells to receptor-mediated cytotoxicity [62]. TRAIL significantly induces apoptosis in both HB cell lines when combined with low concentrations of obatoclax [107]. This effect was moderate with ABT-737, but may be the result of the Mcl-1 expression in HB cells, which can be targeted more effectively using obatoclax. Induction of apoptosis was also significantly enhanced when HuH6 cells were treated with obatoclax in combination with TNF-α. These findings suggest that rather than local administration of tumor necrosis proteins, a broad modulation of apoptotic molecules using BH3-mimetic drugs can be used to sensitize transformed liver cells to TNF-α or TRAIL as previously observed with proteasome inhibitors such as bortezomib or histone deacetylase inhibitors [62,108]. Moreover, TRAIL is critically involved in tumor rejection through cell-mediated immune surveillance. Various immune cells, such as NK cells, T cells, and liver-specific Kupffer cells express TRAIL and mediate apoptosis in infected or transformed cells [109]. In addition, increased expression of stress molecules in tumor cells, such as MICA/B, can be initiated through activation of NK cells by BH3-mimetic drugs. This is then followed by effective tumor cell lysis [35,62]. HB dissemination in the liver was impaired in a mouse model as a result of the interaction of Kupffer cells with HB cells in the presence of BH3-mimetic drugs [107].

8. BH3-Mimetic Drugs as Inhibitors of Tumor Cell Migration

The capacity to migrate and to invade foreign tissues is a common feature of cancer cells dramatically contributing to the malignancy of the disease. Development of metastases in HB also remains a major challenge in treatment. Dissemination and metastasation is closely linked to cell adhesion and cell migration ability, which is also influenced by Bcl-2 proteins [110]. In Bcl-2−/− cells, knockdown of Bcl-2 reduced the cell adhesion of extracellular matrix proteins (ECM). Moreover, knockdown of Bcl-2 impaired the adhesion of ureteric bud cells to vitronectin and fibronectin [111]. In colorectal cancer cells downregulation of Mcl-1, Bcl-xL or Bcl-2 could be demonstrated to lead to a striking impairment of migration and invasion [112]. This is in line with the observation that HB cells adhere less efficiently to matrigel in the presence of ABT-737 or obatoclax, blocking the anti-apoptotic proteins. Similar observations were made with hepatocellular carcinoma cells [113]. Reduced adhesion to ECM may promote or reduce occurence of metastasation depending on the most important events responsible for metastasation in solid tumor cells: detachment from the tumor mass and anchorage of circulating tumor cells to distant tissues. At present, there exist no models to study spontaneous metastasation of HB. However, it could be shown that obatoclax inhibits invasion of HB in the liver in an orthotopic model of HB [107]. In this context, BH3-mimetic drugs are discussed to impair development of lamellipodia in HB cells. Caspases enhance degradation of the GTPase Cdc42, which belongs to the Rho-family and regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression. Other components of the tumor cytoskeleton such as actin, gelsolin, lamin, and plectin are also targets of caspases during early apoptotic events. Moreover, key enzymes, that organize the F-actin network with GTPase activity, are direct substrates of caspase-3 and -7, and play an important role in linking apoptosis to cell motility. BH3-mimetics disrupt the interaction of anti-apoptotic proteins Bcl-2 and Bcl-xL with Beclin-1. Subsequently, the vacant Beclin-1 can trigger the autophagy pathway. However, this has not been studied so far in HB cells.

9. Therapeutic Contribution of BH3-Mimetic Drugs in HB

Survival rates of children with HB depend on prognostic factors such as histological classification, stage, resectability, presence of metastases, AFP levels, patients’ age, and molecular-genetic markers [114,115]. In principle, risk stratification of patients has been improved and has led to encouraging treatment regimens and improved late results [22]. Nevertheless, a group within HR-HB exists, which urgently requires the development of alternative therapeutic strategies. The SIOPEL has modified the risk stratification using the data of more than 1600 patients from international trials collected in a common database CHIC (Children’s Hepatic Tumor International Collaboration) to establish a new international treatment protocol including alternative regiments. In this context, measurement of apoptosis-relevant expression of proteins in patients with HB appears reasonable. Inhibition of Bcl-2 molecules using BH3-mimetic drugs has shown a significant reduction of cell proliferation and tumor growth. This concept has also proven to sensitize immune cells to tumor cells and to inhibit tumor cell dissemination and migration. Consequently, this specific mechanism to restore effectors of apoptosis initiation represents a broad and high level of importance and therefore should be further evaluated in preclinical models as an option for selected HR-HB, especially in those patients presenting with an increased expression of anti-apoptotic proteins.
Currently, obatoclax is under investigation in several clinical trials including those targeting malignant solid tumors. It has been described to be well tolerated without dose-limiting toxicity at 28 mg/m2, although some minor CNS-related side effects have been observed [77,81,116,117]. In addition, a combination therapy using obatoclax together with platin derivates or etoposide has been applied in phase II studies of small cell lung cancer even though some transient side effects have been described in some patients [118]. However, the safety profile of obatoclax makes it an attractive candidate for inclusion in other solid tumor malignancies including childhood HB.
Recently, re-engineering of ABT-263 (navitoclax), creating ABT-199, has been reported by Souers and colleagues [119]. ABT-199 maintains a sub-nanomolar affinity for Bcl-2, but binds at a very significantly less effective level to Bcl-xL. This suggests that the drug may not cause clinically significant thrombocytopenia as described for obatoclax and ABT-263 [117,120]. Suppression of tumor growth by ABT-199 has been described in several human hematological tumor xenograft models with an additive efficacy in combination with traditional cytotoxic agents [121,122,123]. On the other side, tumor lysis after treatment with ABT-199 has been observed to such an extent that potentially serious complications occur. This will have to be critically taken into consideration during a further clinical assessment of this orally bioavailable selective Bcl-2 inhibitor [124].
Including additive BH3-mimetic drugs within existing treatment regimens of HB may lead to dose reduction of traditional cytotoxic drugs and to a reduction of associated immanent side effects, such as nephrotoxicity, ototoxicity and cardiotoxicity while maintaining the antitumor activity at the same time. Furthermore, reduction of tumor growth and inhibition of tumor cell dissemination may presumably facilitate complete surgical tumor resection and improves outcome of HR-HB. Clinical studies should address activation of the immune system in the context of BH3-mimetic drugs as suggested by results of several studies showing various mechanisms of BH3-induced tumor cell death.

10. Conclusions

Treatment optimization through international multicenter trials of HB improved results in SR tumors. In contrast, drug resistance and occurrence of metastases remain the major challenges in the treatment of HR-HB, which urgently requires the development of alternative therapeutic strategies. BH3-mimetic drugs represent a new and promising class of agents in cancer treatment, affecting not only apoptosis modulation but also the immune response and metastases. Convincing preclinical data suggest BH3-mimetics for a clinical trial in pediatric HB.

Author Contributions

Justus Lieber and Sorin Armeanu-Ebinger designed the review, were responsible for figure and table preparation, screened the literature, and wrote the manuscript. Jörg Fuchs revised the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Stiller, C.A.; Pritchard, J.; Steliarova-Foucher, E. Liver cancer in european children: Incidence and survival, 1978–1997. Report from the automated childhood cancer information system project. Eur. J. Cancer 2006, 42, 2115–2123. [Google Scholar] [CrossRef] [PubMed]
  2. Litten, J.B.; Tomlinson, G.E. Liver tumors in children. Oncologist 2008, 13, 812–820. [Google Scholar] [CrossRef] [PubMed]
  3. Pietsch, T.; Fonatsch, C.; Albrecht, S.; Maschek, H.; Wolf, H.K.; von Schweinitz, D. Characterization of the continuous cell line HepT1 derived from a human hepatoblastoma. Lab. Investig. 1996, 74, 809–818. [Google Scholar] [PubMed]
  4. Doi, I. Establishment of a cell line and its clonal sublines from a patient with hepatoblastoma. Gann 1976, 67, 1–10. [Google Scholar] [PubMed]
  5. Katzenstein, H.M.; London, W.B.; Douglass, E.C.; Reynolds, M.; Plaschkes, J.; Finegold, M.J.; Bowman, L.C. Treatment of unresectable and metastatic hepatoblastoma: A pediatric oncology group phase II study. J. Clin. Oncol. 2002, 20, 3438–3444. [Google Scholar] [CrossRef] [PubMed]
  6. Perilongo, G.; Shafford, E.; Maibach, R.; Aronson, D.; Brugieres, L.; Brock, P.; Childs, M.; Czauderna, P.; MacKinlay, G.; Otte, J.B.; et al. Risk-adapted treatment for childhood hepatoblastoma. Final report of the second study of the international society of paediatric oncology—SIOPEL 2. Eur. J. Cancer 2004, 40, 411–421. [Google Scholar] [CrossRef]
  7. Venkatramani, R.; Furman, W.L.; Fuchs, J.; Warmann, S.W.; Malogolowkin, M.H. Current and future management strategies for relapsed or progressive hepatoblastoma. Paediatr. Drugs 2012, 14, 221–232. [Google Scholar] [CrossRef] [PubMed]
  8. Von Schweinitz, D. Management of liver tumors in childhood. Semin. Pediatr. Surg. 2006, 15, 17–24. [Google Scholar]
  9. Douglass, E.C.; Green, A.A.; Wrenn, E.; Champion, J.; Shipp, M.; Pratt, C.B. Effective cisplatin (DDP) based chemotherapy in the treatment of hepatoblastoma. Med. Pediatr. Oncol. 1985, 13, 187–190. [Google Scholar] [CrossRef] [PubMed]
  10. Perilongo, G.; Shafford, E.A. Liver tumours. Eur. J. Cancer 1999, 35, 953–958. [Google Scholar] [CrossRef] [PubMed]
  11. Aronson, D.C.; Schnater, J.M.; Staalman, C.R.; Weverling, G.J.; Plaschkes, J.; Perilongo, G.; Brown, J.; Phillips, A.; Otte, J.B.; Czauderna, P.; et al. Predictive value of the pretreatment extent of disease system in hepatoblastoma: Results from the international society of pediatric oncology liver tumor study group SIOPEL-1 study. J. Clin. Oncol. 2005, 23, 1245–1252. [Google Scholar] [CrossRef]
  12. Meyers, R.L.; Tiao, G.; de Ville de Goyet, J.; Superina, R.; Aronson, D.C. Hepatoblastoma state of the art: Pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation. Curr. Opin. Pediatr. 2014, 26, 29–36. [Google Scholar] [CrossRef] [PubMed]
  13. Brown, J.; Perilongo, G.; Shafford, E.; Keeling, J.; Pritchard, J.; Brock, P.; Dicks-Mireaux, C.; Phillips, A.; Vos, A.; Plaschkes, J. Pretreatment prognostic factors for children with hepatoblastoma—Results from the international society of paediatric oncology (SIOP) study SIOPEL 1. Eur. J. Cancer 2000, 36, 1418–1425. [Google Scholar] [CrossRef] [PubMed]
  14. Perilongo, G.; Maibach, R.; Shafford, E.; Brugieres, L.; Brock, P.; Morland, B.; de Camargo, B.; Zsiros, J.; Roebuck, D.; Zimmermann, A.; et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N. Engl. J. Med. 2009, 361, 1662–1670. [Google Scholar] [CrossRef]
  15. Zsiros, J.; Maibach, R.; Shafford, E.; Brugieres, L.; Brock, P.; Czauderna, P.; Roebuck, D.; Childs, M.; Zimmermann, A.; Laithier, V.; et al. Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: Final results of the SIOPEL-3HR study. J. Clin. Oncol. 2009, 28, 2584–2590. [Google Scholar] [CrossRef]
  16. Fuchs, J.; Rydzynski, J.; von Schweinitz, D.; Bode, U.; Hecker, H.; Weinel, P.; Burger, D.; Harms, D.; Erttmann, R.; Oldhafer, K.; et al. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: A report from the german cooperative pediatric liver tumor study HB 94. Cancer 2002, 95, 172–182. [Google Scholar] [CrossRef]
  17. Haberle, B.; Bode, U.; von Schweinitz, D. Differentiated treatment protocols for high- and standard-risk hepatoblastoma—An interim report of the german liver tumor study HB99. Klin. Padiatr. 2003, 215, 159–165. [Google Scholar] [CrossRef] [PubMed]
  18. Malogolowkin, M.H.; Katzenstein, H.; Krailo, M.D.; Chen, Z.; Bowman, L.; Reynolds, M.; Finegold, M.; Greffe, B.; Rowland, J.; Newman, K.; et al. Intensified platinum therapy is an ineffective strategy for improving outcome in pediatric patients with advanced hepatoblastoma. J. Clin. Oncol. 2006, 24, 2879–2884. [Google Scholar] [CrossRef]
  19. Matsunaga, T.; Sasaki, F.; Ohira, M.; Hashizume, K.; Hayashi, A.; Hayashi, Y.; Mugishima, H.; Ohnuma, N.; Japanese Study Group for Pediatric Liver, T. Analysis of treatment outcome for children with recurrent or metastatic hepatoblastoma. Pediatr. Surg. Int. 2003, 19, 142–146. [Google Scholar] [PubMed]
  20. Ortega, J.A.; Douglass, E.C.; Feusner, J.H.; Reynolds, M.; Quinn, J.J.; Finegold, M.J.; Haas, J.E.; King, D.R.; Liu-Mares, W.; Sensel, M.G.; et al. Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the children’s cancer group and the pediatric oncology group. J. Clin. Oncol. 2000, 18, 2665–2675. [Google Scholar]
  21. Pritchard, J.; Brown, J.; Shafford, E.; Perilongo, G.; Brock, P.; Dicks-Mireaux, C.; Keeling, J.; Phillips, A.; Vos, A.; Plaschkes, J. Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: A successful approach—Results of the first prospective study of the international society of pediatric oncology. J. Clin. Oncol. 2000, 18, 3819–3828. [Google Scholar] [PubMed]
  22. Zsiros, J.; Brugieres, L.; Brock, P.; Roebuck, D.; Maibach, R.; Zimmermann, A.; Childs, M.; Pariente, D.; Laithier, V.; Otte, J.B.; et al. Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study. Lancet Oncol. 2013, 14, 834–842. [Google Scholar] [CrossRef]
  23. Czauderna, P.; Otte, J.B.; Aronson, D.C.; Gauthier, F.; Mackinlay, G.; Roebuck, D.; Plaschkes, J.; Perilongo, G. Guidelines for surgical treatment of hepatoblastoma in the modern era—Recommendations from the childhood liver tumour strategy group of the international society of paediatric oncology (SIOPEL). Eur. J. Cancer 2005, 41, 1031–1036. [Google Scholar] [CrossRef] [PubMed]
  24. Otte, J.B.; de Ville de Goyet, J.; Reding, R. Liver transplantation for hepatoblastoma: Indications and contraindications in the modern era. Pediatr. Transplant. 2005, 9, 557–565. [Google Scholar] [CrossRef] [PubMed]
  25. Grotegut, S.; Kappler, R.; Tarimoradi, S.; Lehembre, F.; Christofori, G.; von Schweinitz, D. Hepatocyte growth factor protects hepatoblastoma cells from chemotherapy-induced apoptosis by akt activation. Int. J. Oncol. 2010, 36, 1261–1267. [Google Scholar] [PubMed]
  26. Warmann, S.W.; Armeanu, S.; Heigoldt, H.; Ruck, P.; Vonthein, R.; Heitmann, H.; Seitz, G.; Lemken, M.L.; Bitzer, M.; Fuchs, J.; et al. Adenovirus-mediated cytosine deaminase/5-fluorocytosine suicide gene therapy of human hepatoblastoma in vitro. Pediatr. Blood Cancer 2009, 53, 145–151. [Google Scholar] [CrossRef]
  27. Eicher, C.; Dewerth, A.; Thomale, J.; Ellerkamp, V.; Hildenbrand, S.; Warmann, S.W.; Fuchs, J.; Armeanu-Ebinger, S. Effect of sorafenib combined with cytostatic agents on hepatoblastoma cell lines and xenografts. Br. J. Cancer 2013, 108, 334–341. [Google Scholar] [CrossRef] [PubMed]
  28. Hartmann, W.; Kuchler, J.; Koch, A.; Friedrichs, N.; Waha, A.; Endl, E.; Czerwitzki, J.; Metzger, D.; Steiner, S.; Wurst, P.; et al. Activation of phosphatidylinositol-3'-kinase/Akt signaling is essential in hepatoblastoma survival. Clin. Cancer Res. 2009, 15, 4538–4545. [Google Scholar] [CrossRef]
  29. McConkey, D.J.; Zhu, K. Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist. Updat. 2008, 11, 164–179. [Google Scholar] [CrossRef] [PubMed]
  30. Humeniuk, R.; Mishra, P.J.; Bertino, J.R.; Banerjee, D. Molecular targets for epigenetic therapy of cancer. Curr. Pharm. Biotechnol. 2009, 10, 161–165. [Google Scholar] [CrossRef] [PubMed]
  31. Tan, M.L.; Ooi, J.P.; Ismail, N.; Moad, A.I.; Muhammad, T.S. Programmed cell death pathways and current antitumor targets. Pharm. Res. 2009, 26, 1547–1560. [Google Scholar] [CrossRef] [PubMed]
  32. Warmann, S.W.; Frank, H.; Heitmann, H.; Ruck, P.; Herberts, T.; Seitz, G.; Fuchs, J. Bcl-2 gene silencing in pediatric epithelial liver tumors. J. Surg. Res. 2008, 144, 43–48. [Google Scholar] [CrossRef] [PubMed]
  33. Kobrinsky, N.L.; Sjolander, D.E.; Goldenberg, J.A.; Ortmeier, T.C. Successful treatment of doxorubicin and cisplatin resistant hepatoblastoma in a child with beckwith-wiedemann syndrome with high dose acetaminophen and N-acetylcysteine rescue. Pediatr. Blood Cancer 2005, 45, 222–225. [Google Scholar] [CrossRef] [PubMed]
  34. Inaba, H.; Handgretinger, R.; Furman, W.; Hale, G.; Leung, W. Allogeneic graft-versus-hepatoblastoma effect. Pediatr. Blood Cancer 2006, 46, 501–505. [Google Scholar] [CrossRef] [PubMed]
  35. Armeanu, S.; Bitzer, M.; Lauer, U.M.; Venturelli, S.; Pathil, A.; Krusch, M.; Kaiser, S.; Jobst, J.; Smirnow, I.; Wagner, A.; et al. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 2005, 65, 6321–6329. [Google Scholar] [CrossRef]
  36. Hoh, A.; Dewerth, A.; Vogt, F.; Wenz, J.; Baeuerle, P.A.; Warmann, S.W.; Fuchs, J.; Armeanu-Ebinger, S. The activity of gammadelta T cells against paediatric liver tumour cells and spheroids in cell culture. Liver Int. 2013, 33, 127–136. [Google Scholar] [CrossRef] [PubMed]
  37. Chang, J.F.; Chen, P.J.; Sze, D.Y.; Reid, T.; Bartlett, D.; Kirn, D.H.; Liu, T.C. Oncolytic virotherapy for advanced liver tumours. J. Cell. Mol. Med. 2009, 13, 1238–1247. [Google Scholar] [CrossRef] [PubMed]
  38. Warmann, S.W.; Armeanu, S.; Frank, H.; Buck, H.; Graepler, F.; Lemken, M.L.; Heitmann, H.; Seitz, G.; Lauer, U.M.; Bitzer, M.; et al. In vitro gene targeting in human hepatoblastoma. Pediatr. Surg. Int. 2006, 22, 16–23. [Google Scholar]
  39. Von Schweinitz, D.; Hecker, H.; Schmidt-von-Arndt, G.; Harms, D. Prognostic factors and staging systems in childhood hepatoblastoma. Int. J. Cancer 1997, 74, 593–599. [Google Scholar] [CrossRef] [PubMed]
  40. Chu, G. Cellular responses to cisplatin. The roles of DNA-binding proteins and DNA repair. J. Biol. Chem. 1994, 269, 787–790. [Google Scholar] [PubMed]
  41. Oue, T.; Yoneda, A.; Uehara, S.; Yamanaka, H.; Fukuzawa, M. Increased expression of multidrug resistance-associated genes after chemotherapy in pediatric solid malignancies. J. Pediatr. Surg. 2009, 44, 377–380. [Google Scholar] [CrossRef] [PubMed]
  42. Pommier, Y.; Leteurtre, F.; Fesen, M.R.; Fujimori, A.; Bertrand, R.; Solary, E.; Kohlhagen, G.; Kohn, K.W. Cellular determinants of sensitivity and resistance to DNA topoisomerase inhibitors. Cancer Investig. 1994, 12, 530–542. [Google Scholar] [CrossRef]
  43. Townsend, D.M.; Tew, K.D. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 2003, 22, 7369–7375. [Google Scholar] [CrossRef] [PubMed]
  44. Sigal, A.; Rotter, V. Oncogenic mutations of the p53 tumor suppressor: The demons of the guardian of the genome. Cancer Res. 2000, 60, 6788–6793. [Google Scholar] [PubMed]
  45. Wong, R.S. Apoptosis in cancer: From pathogenesis to treatment. J. Exp. Clin. Cancer Res. 2011, 30, 87. [Google Scholar] [CrossRef] [PubMed]
  46. Chonghaile, T.N.; Letai, A. Mimicking the BH3 domain to kill cancer cells. Oncogene 2008, 27, S149–S157. [Google Scholar] [CrossRef] [PubMed]
  47. Chittenden, T.; Harrington, E.A.; O’Connor, R.; Flemington, C.; Lutz, R.J.; Evan, G.I.; Guild, B.C. Induction of apoptosis by the Bcl-2 homologue bak. Nature 1995, 374, 733–736. [Google Scholar] [CrossRef] [PubMed]
  48. Gibson, L.; Holmgreen, S.P.; Huang, D.C.; Bernard, O.; Copeland, N.G.; Jenkins, N.A.; Sutherland, G.R.; Baker, E.; Adams, J.M.; Cory, S. Bcl-w, a novel member of the Bcl-2 family, promotes cell survival. Oncogene 1996, 13, 665–675. [Google Scholar] [PubMed]
  49. Nakano, K.; Vousden, K.H. Puma, a novel proapoptotic gene, is induced by p53. Mol. Cell 2001, 7, 683–694. [Google Scholar] [CrossRef] [PubMed]
  50. Wei, M.C.; Lindsten, T.; Mootha, V.K.; Weiler, S.; Gross, A.; Ashiya, M.; Thompson, C.B.; Korsmeyer, S.J. Tbid, a membrane-targeted death ligand, oligomerizes bak to release cytochrome c. Genes Dev. 2000, 14, 2060–2071. [Google Scholar] [PubMed]
  51. Oda, E.; Ohki, R.; Murasawa, H.; Nemoto, J.; Shibue, T.; Yamashita, T.; Tokino, T.; Taniguchi, T.; Tanaka, N. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000, 288, 1053–1058. [Google Scholar] [CrossRef] [PubMed]
  52. Eskes, R.; Desagher, S.; Antonsson, B.; Martinou, J.C. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol. Cell. Biol. 2000, 20, 929–935. [Google Scholar] [CrossRef] [PubMed]
  53. Korsmeyer, S.J.; Wei, M.C.; Saito, M.; Weiler, S.; Oh, K.J.; Schlesinger, P.H. Pro-apoptotic cascade activates bid, which oligomerizes Bak or Bax into pores that result in the release of cytochrome c. Cell Death Differ. 2000, 7, 1166–1173. [Google Scholar] [CrossRef] [PubMed]
  54. Kim, H.; Rafiuddin-Shah, M.; Tu, H.C.; Jeffers, J.R.; Zambetti, G.P.; Hsieh, J.J.; Cheng, E.H. Hierarchical regulation of mitochondrion-dependent apoptosis by Bcl-2 subfamilies. Nat. Cell Biol. 2006, 8, 1348–1358. [Google Scholar] [CrossRef] [PubMed]
  55. Letai, A.; Bassik, M.C.; Walensky, L.D.; Sorcinelli, M.D.; Weiler, S.; Korsmeyer, S.J. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002, 2, 183–192. [Google Scholar] [CrossRef] [PubMed]
  56. Kang, M.H.; Reynolds, C.P. Bcl-2 inhibitors: Targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 2009, 15, 1126–1132. [Google Scholar] [CrossRef] [PubMed]
  57. Youle, R.J.; Strasser, A. The Bcl-2 protein family: Opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 2008, 9, 47–59. [Google Scholar] [CrossRef] [PubMed]
  58. Bagnoli, M.; Canevari, S.; Mezzanzanica, D. Cellular FLICE-inhibitory protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer. Int. J. Biochem. Cell Biol. 2009, 42, 210–213. [Google Scholar] [CrossRef] [PubMed]
  59. Safa, A.R.; Day, T.W.; Wu, C.H. Cellular FLICE-like inhibitory protein (c-FLIP): A novel target for cancer therapy. Curr. Cancer Drug Targets 2008, 8, 37–46. [Google Scholar] [CrossRef] [PubMed]
  60. Adesina, A.M.; Lopez-Terrada, D.; Wong, K.K.; Gunaratne, P.; Nguyen, Y.; Pulliam, J.; Margolin, J.; Finegold, M.J. Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum. Pathol. 2009, 40, 843–853. [Google Scholar] [CrossRef] [PubMed]
  61. Lieber, J.; Kirchner, B.; Eicher, C.; Warmann, S.W.; Seitz, G.; Fuchs, J.; Armeanu-Ebinger, S. Inhibition of Bcl-2 and Bcl-x enhances chemotherapy sensitivity in hepatoblastoma cells. Pediatr. Blood Cancer 2010, 55, 1089–1095. [Google Scholar] [CrossRef] [PubMed]
  62. Armeanu-Ebinger, S.; Fuchs, J.; Wenz, J.; Seitz, G.; Ruck, P.; Warmann, S.W. Proteasome inhibition overcomes trail resistance in human hepatoblastoma cells. Front. Biosci. 2012, 4, 2194–2202. [Google Scholar] [CrossRef]
  63. Cotter, F.E.; Johnson, P.; Hall, P.; Pocock, C.; al Mahdi, N.; Cowell, J.K.; Morgan, G. Antisense oligonucleotides suppress B-cell lymphoma growth in a scid-hu mouse model. Oncogene 1994, 9, 3049–3055. [Google Scholar] [PubMed]
  64. Chan, S.L.; Lee, M.C.; Tan, K.O.; Yang, L.K.; Lee, A.S.; Flotow, H.; Fu, N.Y.; Butler, M.S.; Soejarto, D.D.; Buss, A.D.; et al. Identification of chelerythrine as an inhibitor of bclxl function. J. Biol. Chem. 2003, 278, 20453–20456. [Google Scholar] [CrossRef] [PubMed]
  65. Zhai, D.; Jin, C.; Satterthwait, A.C.; Reed, J.C. Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ. 2006, 13, 1419–1421. [Google Scholar] [CrossRef] [PubMed]
  66. Doi, K.; Li, R.; Sung, S.S.; Wu, H.; Liu, Y.; Manieri, W.; Krishnegowda, G.; Awwad, A.; Dewey, A.; Liu, X.; et al. Discovery of marinopyrrole a (maritoclax) as a selective MCL-1 antagonist that overcomes ABT-737 resistance by binding to and targeting MCL-1 for proteasomal degradation. J. Biol. Chem. 2012, 287, 10224–10235. [Google Scholar] [CrossRef] [PubMed]
  67. Oltersdorf, T.; Elmore, S.W.; Shoemaker, A.R.; Armstrong, R.C.; Augeri, D.J.; Belli, B.A.; Bruncko, M.; Deckwerth, T.L.; Dinges, J.; Hajduk, P.J.; et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005, 435, 677–681. [Google Scholar] [CrossRef] [PubMed]
  68. Muchmore, S.W.; Sattler, M.; Liang, H.; Meadows, R.P.; Harlan, J.E.; Yoon, H.S.; Nettesheim, D.; Chang, B.S.; Thompson, C.B.; Wong, S.L.; et al. X-ray and nmr structure of human Bcl-xl, an inhibitor of programmed cell death. Nature 1996, 381, 335–341. [Google Scholar] [CrossRef] [PubMed]
  69. Lock, R.; Carol, H.; Houghton, P.J.; Morton, C.L.; Kolb, E.A.; Gorlick, R.; Reynolds, C.P.; Maris, J.M.; Keir, S.T.; Wu, J.; et al. Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr. Blood Cancer 2008, 50, 1181–1189. [Google Scholar] [CrossRef] [PubMed]
  70. Schelman, W.R.; Mohammed, T.A.; Traynor, A.M.; Kolesar, J.M.; Marnocha, R.M.; Eickhoff, J.; Keppen, M.; Alberti, D.B.; Wilding, G.; Takebe, N.; et al. A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer. Investig. New Drugs 2014, 32, 295–302. [Google Scholar] [CrossRef]
  71. Schimmer, A.D.; Raza, A.; Carter, T.H.; Claxton, D.; Erba, H.; de Angelo, D.J.; Tallman, M.S.; Goard, C.; Borthakur, G. A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia. PLoS One 2014, 9, e108694. [Google Scholar] [CrossRef] [PubMed]
  72. Modugno, M.; Banfi, P.; Gasparri, F.; Borzilleri, R.; Carter, P.; Cornelius, L.; Gottardis, M.; Lee, V.; Mapelli, C.; Naglich, J.G.; et al. MCL-1 antagonism is a potential therapeutic strategy in a subset of solid cancers. Exp. Cell. Res. 2014. [Google Scholar] [CrossRef]
  73. Molica, S. Progress in the treatment of elderly/unfit chronic lymphocytic leukemia patients: Results of the german CLL-11 trial. Expert Rev. Anticancer Ther. 2015, 15, 9–15. [Google Scholar] [CrossRef] [PubMed]
  74. Arellano, M.L.; Borthakur, G.; Berger, M.; Luer, J.; Raza, A. A phase ii, multicenter, open-label study of obatoclax mesylate in patients with previously untreated myelodysplastic syndromes with anemia or thrombocytopenia. Clin. Lymphoma Myeloma Leukemia 2014, 14, 534–539. [Google Scholar] [CrossRef]
  75. Arisan, E.D.; Kutuk, O.; Tezil, T.; Bodur, C.; Telci, D.; Basaga, H. Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells. Breast Cancer Res. Treat. 2010, 119, 271–281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Ashimori, N.; Zeitlin, B.D.; Zhang, Z.; Warner, K.; Turkienicz, I.M.; Spalding, A.C.; Teknos, T.N.; Wang, S.; Nor, J.E. Tw-37, a small-molecule inhibitor of Bcl-2, mediates s-phase cell cycle arrest and suppresses head and neck tumor angiogenesis. Mol. Cancer Ther. 2009, 8, 893–903. [Google Scholar] [CrossRef] [PubMed]
  77. Konopleva, M.; Watt, J.; Contractor, R.; Tsao, T.; Harris, D.; Estrov, Z.; Bornmann, W.; Kantarjian, H.; Viallet, J.; Samudio, I.; et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic Gx15-070 (obatoclax). Cancer Res. 2008, 68, 3413–3420. [Google Scholar] [CrossRef] [PubMed]
  78. Mason, K.D.; Khaw, S.L.; Rayeroux, K.C.; Chew, E.; Lee, E.F.; Fairlie, W.D.; Grigg, A.P.; Seymour, J.F.; Szer, J.; Huang, D.C.; et al. The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia 2009, 23, 2034–2041. [Google Scholar] [CrossRef] [PubMed]
  79. Mohammad, R.M.; Goustin, A.S.; Aboukameel, A.; Chen, B.; Banerjee, S.; Wang, G.; Nikolovska-Coleska, Z.; Wang, S.; Al-Katib, A. Preclinical studies of Tw-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphoma xenograft model reveal drug action on both Bcl-2 and Mcl-1. Clin. Cancer Res. 2007, 13, 2226–2235. [Google Scholar] [CrossRef] [PubMed]
  80. Oliver, L.; Mahe, B.; Gree, R.; Vallette, F.M.; Juin, P. HA14-1, a small molecule inhibitor of Bcl-2, bypasses chemoresistance in leukaemia cells. Leuk. Res. 2007, 31, 859–863. [Google Scholar] [CrossRef] [PubMed]
  81. Trudel, S.; Stewart, A.K.; Li, Z.; Shu, Y.; Liang, S.B.; Trieu, Y.; Reece, D.; Paterson, J.; Wang, D.; Wen, X.Y. The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin. Cancer Res. 2007, 13, 621–629. [Google Scholar] [CrossRef] [PubMed]
  82. Champa, D.; Russo, M.A.; Liao, X.H.; Refetoff, S.; Ghossein, R.A.; di Cristofano, A. Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering BCL2A1 and MCL1 overexpression. Endocr. Relat. Cancer 2014, 21, 755–767. [Google Scholar] [CrossRef] [PubMed]
  83. Koehler, B.C.; Scherr, A.L.; Lorenz, S.; Elssner, C.; Kautz, N.; Welte, S.; Jaeger, D.; Urbanik, T.; Schulze-Bergkamen, H. Pan-Bcl-2 inhibitor obatoclax delays cell cycle progression and blocks migration of colorectal cancer cells. PLoS One 2014, 9, e106571. [Google Scholar] [CrossRef] [PubMed]
  84. Vogler, M.; Weber, K.; Dinsdale, D.; Schmitz, I.; Schulze-Osthoff, K.; Dyer, M.J.; Cohen, G.M. Different forms of cell death induced by putative Bcl2 inhibitors. Cell Death Differ. 2009, 16, 1030–1039. [Google Scholar] [CrossRef] [PubMed]
  85. Lieber, J.; Ellerkamp, V.; Wenz, J.; Kirchner, B.; Warmann, S.W.; Fuchs, J.; Armeanu-Ebinger, S. Apoptosis sensitizers enhance cytotoxicity in hepatoblastoma cells. Pediatr. Surg. Int. 2011, 28, 149–159. [Google Scholar] [CrossRef]
  86. Lieber, J.; Dewerth, A.; Wenz, J.; Kirchner, B.; Eicher, C.; Warmann, S.W.; Fuchs, J.; Armeanu-Ebinger, S. Increased efficacy of CDDP in a xenograft model of hepatoblastoma using the apoptosis sensitizer ABT-737. Oncol. Rep. 2013, 29, 646. [Google Scholar] [PubMed]
  87. Lieber, J.; Eicher, C.; Wenz, J.; Kirchner, B.; Warmann, S.W.; Fuchs, J.; Armeanu-Ebinger, S. The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma. BMC Cancer 2011, 11, 362. [Google Scholar] [CrossRef] [PubMed]
  88. Kim, H.; Tu, H.C.; Ren, D.; Takeuchi, O.; Jeffers, J.R.; Zambetti, G.P.; Hsieh, J.J.; Cheng, E.H. Stepwise activation of Bax and Bak by tBid, Bim, and puma initiates mitochondrial apoptosis. Mol. Cell 2009, 36, 487–499. [Google Scholar] [CrossRef] [PubMed]
  89. Skommer, J.; Brittain, T.; Raychaudhuri, S. Bcl-2 inhibits apoptosis by increasing the time-to-death and intrinsic cell-to-cell variations in the mitochondrial pathway of cell death. Apoptosis 2010, 15, 1223–1233. [Google Scholar] [CrossRef] [PubMed]
  90. Griffiths, G.J.; Dubrez, L.; Morgan, C.P.; Jones, N.A.; Whitehouse, J.; Corfe, B.M.; Dive, C.; Hickman, J.A. Cell damage-induced conformational changes of the pro-apoptotic protein bak in vivo precede the onset of apoptosis. J. Cell Biol. 1999, 144, 903–914. [Google Scholar] [CrossRef] [PubMed]
  91. Analysis, R.R.D.f.G.E. Available online: http://157.82.78.238/refexa/main_search.Jsp%5D (accessed on 10 January 2015).
  92. E-MEXP-1851, D. Available online: http://www.Ebi.Ac.Uk/arrayexpress%5D (accessed on 15 August 2012).
  93. Malogolowkin, M.H.; Katzenstein, H.M.; Krailo, M.; Chen, Z.; Quinn, J.J.; Reynolds, M.; Ortega, J.A. Redefining the role of doxorubicin for the treatment of children with hepatoblastoma. J. Clin. Oncol. 2008, 26, 2379–2383. [Google Scholar] [CrossRef] [PubMed]
  94. Wang, J.L.; Liu, D.; Zhang, Z.J.; Shan, S.; Han, X.; Srinivasula, S.M.; Croce, C.M.; Alnemri, E.S.; Huang, Z. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc. Natl. Acad. Sci. USA 2000, 97, 7124–7129. [Google Scholar] [CrossRef] [PubMed]
  95. Jane, E.P.; Premkumar, D.R.; Morales, A.; Foster, K.A.; Pollack, I.F. Inhibition of phosphatidylinositol 3-kinase/Akt signaling by Nvp-Bkm120 promotes ABT-737-induced toxicity in a caspase-dependent manner through mitochondrial dysfunction and DNA damage response in established and primary cultured glioblastoma cells. J. Pharmacol. Exp. Ther. 2014, 350, 22–35. [Google Scholar] [CrossRef] [PubMed]
  96. Lickliter, J.D.; Wood, N.J.; Johnson, L.; McHugh, G.; Tan, J.; Wood, F.; Cox, J.; Wickham, N.W. HA14-1 selectively induces apoptosis in Bcl-2-overexpressing leukemia/lymphoma cells, and enhances cytarabine-induced cell death. Leukemia 2003, 17, 2074–2080. [Google Scholar] [CrossRef] [PubMed]
  97. Manero, F.; Gautier, F.; Gallenne, T.; Cauquil, N.; Gree, D.; Cartron, P.F.; Geneste, O.; Gree, R.; Vallette, F.M.; Juin, P. The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death. Cancer Res. 2006, 66, 2757–2764. [Google Scholar] [CrossRef] [PubMed]
  98. Niizuma, H.; Nakamura, Y.; Ozaki, T.; Nakanishi, H.; Ohira, M.; Isogai, E.; Kageyama, H.; Imaizumi, M.; Nakagawara, A. Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma. Oncogene 2006, 25, 5046–5055. [Google Scholar] [CrossRef] [PubMed]
  99. Hermanson, D.; Addo, S.N.; Bajer, A.A.; Marchant, J.S.; Das, S.G.; Srinivasan, B.; Al-Mousa, F.; Michelangeli, F.; Thomas, D.D.; Lebien, T.W.; et al. Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria. Mol. Pharmacol. 2009, 76, 667–678. [Google Scholar] [CrossRef] [PubMed]
  100. Pei, X.Y.; Dai, Y.; Grant, S. The small-molecule Bcl-2 inhibitor HA14-1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and Jun NH2-terminal kinase-dependent mechanism. Mol. Cancer Ther. 2004, 3, 1513–1524. [Google Scholar] [PubMed]
  101. Doshi, J.M.; Tian, D.; Xing, C. Ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4h-chromene-3-carboxylate (HA 14-1), a prototype small-molecule antagonist against antiapoptotic Bcl-2 proteins, decomposes to generate reactive oxygen species that induce apoptosis. Mol. Pharm. 2007, 4, 919–928. [Google Scholar] [CrossRef] [PubMed]
  102. Tian, D.; Das, S.G.; Doshi, J.M.; Peng, J.; Lin, J.; Xing, C. Sha 14-1, a stable and ros-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell. Cancer Lett. 2008, 259, 198–208. [Google Scholar] [CrossRef] [PubMed]
  103. Wang, G.; Nikolovska-Coleska, Z.; Yang, C.Y.; Wang, R.; Tang, G.; Guo, J.; Shangary, S.; Qiu, S.; Gao, W.; Yang, D.; et al. Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J. Med. Chem. 2006, 49, 6139–6142. [Google Scholar] [CrossRef] [PubMed]
  104. Forastiere, A.A. Chemotherapy in the treatment of locally advanced head and neck cancer. J. Surg. Oncol. 2008, 97, 701–707. [Google Scholar] [CrossRef] [PubMed]
  105. Lejeune, F.J.; Lienard, D.; Matter, M.; Ruegg, C. Efficiency of recombinant human TNF in human cancer therapy. Cancer Immun. 2006, 6, 6. [Google Scholar] [PubMed]
  106. Nakamoto, T.; Inagawa, H.; Takagi, K.; Soma, G. A new method of antitumor therapy with a high dose of TNF perfusion for unresectable liver tumors. Anticancer Res. 2000, 20, 4087–4096. [Google Scholar] [PubMed]
  107. Lieber, J.; Ellerkamp, V.; Vogt, F.; Wenz, J.; Warmann, S.W.; Fuchs, J.; Armeanu-Ebinger, S. BH3-mimetic drugs prevent tumour onset in an orthotopic mouse model of hepatoblastoma. Exp. Cell Res. 2014, 322, 217–225. [Google Scholar] [CrossRef] [PubMed]
  108. Pathil, A.; Armeanu, S.; Venturelli, S.; Mascagni, P.; Weiss, T.S.; Gregor, M.; Lauer, U.M.; Bitzer, M. Hdac inhibitor treatment of hepatoma cells induces both trail-independent apoptosis and restoration of sensitivity to trail. Hepatology 2006, 43, 425–434. [Google Scholar] [CrossRef] [PubMed]
  109. Wajant, H. The fas signaling pathway: More than a paradigm. Science 2002, 296, 1635–1636. [Google Scholar] [CrossRef] [PubMed]
  110. Grutzmacher, C.; Park, S.; Elmergreen, T.L.; Tang, Y.; Scheef, E.A.; Sheibani, N.; Sorenson, C.M. Opposing effects of bim and Bcl-2 on lung endothelial cell migration. Am. J. Physiol. Lung Cell. Mol. Physiol. 2010, 299, L607–L620. [Google Scholar] [CrossRef] [PubMed]
  111. Sheibani, N.; Scheef, E.A.; Dimaio, T.A.; Wang, Y.; Kondo, S.; Sorenson, C.M. Bcl-2 expression modulates cell adhesion and migration promoting branching of ureteric bud cells. J. Cell. Physiol. 2007, 210, 616–625. [Google Scholar] [CrossRef] [PubMed]
  112. Koehler, B.C.; Scherr, A.L.; Lorenz, S.; Urbanik, T.; Kautz, N.; Elssner, C.; Welte, S.; Bermejo, J.L.; Jager, D.; Schulze-Bergkamen, H. Beyond cell death—Antiapoptotic Bcl-2 proteins regulate migration and invasion of colorectal cancer cells in vitro. PLoS One 2013, 8, e76446. [Google Scholar] [CrossRef] [PubMed]
  113. Vogt, F.; Lieber, J.; Dewerth, A.; Hoh, A.; Fuchs, J.; Armeanu-Ebinger, S. BH3 mimetics reduce adhesion and migration of hepatoblastoma and hepatocellular carcinoma cells. Exp. Cell Res. 2013, 319, 1443–1450. [Google Scholar] [CrossRef] [PubMed]
  114. Koch, A.; Waha, A.; Hartmann, W.; Hrychyk, A.; Schuller, U.; Wharton, K.A., Jr.; Fuchs, S.Y.; von Schweinitz, D.; Pietsch, T. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin. Cancer Res. 2005, 11, 4295–4304. [Google Scholar] [CrossRef] [PubMed]
  115. Von Schweinitz, D.; Kraus, J.A.; Albrecht, S.; Koch, A.; Fuchs, J.; Pietsch, T. Prognostic impact of molecular genetic alterations in hepatoblastoma. Med. Pediatr. Oncol. 2002, 38, 104–108. [Google Scholar] [CrossRef] [PubMed]
  116. Hwang, J.J.; Kuruvilla, J.; Mendelson, D.; Pishvaian, M.J.; Deeken, J.F.; Siu, L.L.; Berger, M.S.; Viallet, J.; Marshall, J.L. Phase i dose finding studies of obatoclax (Gx15–070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin. Cancer Res. 2010, 16, 4038–4045. [Google Scholar] [CrossRef] [PubMed]
  117. Schimmer, A.D.; O’Brien, S.; Kantarjian, H.; Brandwein, J.; Cheson, B.D.; Minden, M.D.; Yee, K.; Ravandi, F.; Giles, F.; Schuh, A.; et al. A phase i study of the pan Bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin. Cancer Res. 2008, 14, 8295–8301. [Google Scholar] [CrossRef] [PubMed]
  118. Langer, C.J.; Albert, I.; Ross, H.J.; Kovacs, P.; Blakely, L.J.; Pajkos, G.; Somfay, A.; Zatloukal, P.; Kazarnowicz, A.; Moezi, M.M.; et al. Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer. Lung Cancer 2014, 85, 420–428. [Google Scholar] [CrossRef] [PubMed]
  119. Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; et al. ABT-199, a potent and selective Bcl-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 2013, 19, 202–208. [Google Scholar] [CrossRef] [PubMed]
  120. Kaefer, A.; Yang, J.; Noertersheuser, P.; Mensing, S.; Humerickhouse, R.; Awni, W.; Xiong, H. Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother. Pharmacol. 2014, 74, 593–602. [Google Scholar] [CrossRef] [PubMed]
  121. Johnson-Farley, N.; Veliz, J.; Bhagavathi, S.; Bertino, J.R. ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib, and JQ1 in “double hit” lymphoma cells. Leukemia Lymphoma 2014, 1, 1–12. [Google Scholar]
  122. Peirs, S.; Matthijssens, F.; Goossens, S.; van de Walle, I.; Ruggero, K.; de Bock, C.E.; Degryse, S.; Cante-Barrett, K.; Briot, D.; Clappier, E.; et al. ABT-199 mediated inhibition of Bcl-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood 2014, 124, 3738–3747. [Google Scholar] [CrossRef] [PubMed]
  123. Zeuner, A.; Francescangeli, F.; Contavalli, P.; Zapparelli, G.; Apuzzo, T.; Eramo, A.; Baiocchi, M.; de Angelis, M.L.; Biffoni, M.; Sette, G.; et al. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-xl inhibition in non-small cell lung cancer. Cell Death Differ. 2014, 21, 1877–1888. [Google Scholar] [CrossRef] [PubMed]
  124. Davids, M.S.; Letai, A. ABT-199: Taking dead aim at Bcl-2. Cancer Cell 2013, 23, 139–141. [Google Scholar] [CrossRef] [PubMed]

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MDPI and ACS Style

Lieber, J.; Armeanu-Ebinger, S.; Fuchs, J. The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma. Int. J. Mol. Sci. 2015, 16, 4190-4208. https://doi.org/10.3390/ijms16024190

AMA Style

Lieber J, Armeanu-Ebinger S, Fuchs J. The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma. International Journal of Molecular Sciences. 2015; 16(2):4190-4208. https://doi.org/10.3390/ijms16024190

Chicago/Turabian Style

Lieber, Justus, Sorin Armeanu-Ebinger, and Jörg Fuchs. 2015. "The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma" International Journal of Molecular Sciences 16, no. 2: 4190-4208. https://doi.org/10.3390/ijms16024190

APA Style

Lieber, J., Armeanu-Ebinger, S., & Fuchs, J. (2015). The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma. International Journal of Molecular Sciences, 16(2), 4190-4208. https://doi.org/10.3390/ijms16024190

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