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Biomolecules
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Novel Molecules for Cancer Treatment (3rd Edition)
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Novel Molecules for Cancer Treatment (3rd Edition)

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-derived Molecules".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 540

Special Issue Editor

Dr. Javier Martínez Useros

E-Mail Website
Guest Editor
OncoHealth Institute, Health Research Institute-Fundacion Jimenez Diaz University Hospital, Autonomous University, 28040 Madrid, Spain
Interests: gastric cancer; pancreatic cancer; colorectal cancer; metastatic melanoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer can appear anywhere in the body due to the accumulation of mutations and other genomic aberrations that lead to uncontrolled cell proliferation, the inhibition of apoptosis, and increased cell migration. Tumor cells are able to activate via mechanisms that generate tumors and develop metastases through the induction of the epithelial-to-mesenchymal transition, angiogenesis, and an immunosuppressive microenvironment. Other crucial events in tumorigenesis are the emergence of the undifferentiated phenotype, in addition to the generation and maintenance of cancer stem cells. In carcinogenesis, the coactivation of several genes and pathways is common, and the study of these factors and signaling pathways has enabled the identification of novel targets for the design of drugs. These drugs could be chemically synthesized or isolated from natural substances and represent a signficant advancement in realizing personalized medicine in present clinical practice.

In this Special Issue, entitled "Novel Molecules for Cancer Treatment (3rd Edition)", we encourage authors to submit high-quality research articles that address novel biomolecules and provide the scientific and clinical communities with strong evidence of their antitumor activity. This activity could be observed in both solid tumors and in hematological malignancies, and could be evaluated with in vitro and/or in vivo models. On the other hand, we are open to receiving updated reviews concerning novel molecules or treatment strategies based on synthetic or natural compounds and that provide a basis for further translational oncological research.

I look forward to receiving your manuscripts.

Dr. Javier Martínez Useros
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer
  • small molecules
  • antibody-drug-conjugated
  • tyrosine kinase inhibitors
  • target therapy
  • monoclonal antibodies
  • immunotherapy
  • natural compounds

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Research

21 pages, 8334 KiB  
Article
A Phosphatidyl Conjugated Telomerase-Dependent Telomere-Targeting Nucleoside Demonstrates Colorectal Cancer Direct Killing and Immune Signaling
by Merve Yilmaz, Sibel Goksen, Ilgen Mender, Gunes Esendagli, Sefik Evren Erdener, Alessandra Ahmed, Ates Kutay Tenekeci, Larisa L. Birichevskaya, Sergei M. Gryaznov, Jerry W. Shay and Z. Gunnur Dikmen
Biomolecules 2024, 14(12), 1616; https://doi.org/10.3390/biom14121616 - 18 Dec 2024
Viewed by 426
Abstract
Telomerase and telomeres are crucial in cancer cell immortalization, making them key targets for anticancer therapies. Currently, 6-thio-dG (THIO) combined with the anti-PD-1 inhibitor Cemiplimab is under phase II clinical investigation (NCT05208944) in NSCLC patients resistant to prior immunotherapies. This study presents the [...] Read more.
Telomerase and telomeres are crucial in cancer cell immortalization, making them key targets for anticancer therapies. Currently, 6-thio-dG (THIO) combined with the anti-PD-1 inhibitor Cemiplimab is under phase II clinical investigation (NCT05208944) in NSCLC patients resistant to prior immunotherapies. This study presents the design, synthesis, and evaluation of novel bimodular conjugate molecules combining telomere-targeting nucleoside analogs and phosphatidyl diglyceride groups. Among them, dihexanoyl-phosphatidyl-THIO (diC6-THIO) showed high anticancer activity with sub-µM EC50 values in vitro across various cancer cell lines. In mouse colorectal cancer models, diC6-THIO demonstrated strong anticancer effects alone and in combination with PD1/PD-L1 inhibitors. Administration of this compound resulted in the efficient formation of Telomere dysfunction Induced Foci (TIFs) in vitro, indicating an on-target, telomerase-mediated telomere-modifying mechanism of action for the molecule. Systemic treatment also activated CD4+ and CD8+ T cells while reducing regulatory T cells, indicating immune system enhancement. Notably, diC6-THIO exhibits an improved solubility profile while maintaining comparable anticancer properties, further supporting its potential as a promising therapeutic candidate. These findings highlight diC6-THIO as a promising telomere-targeting prodrug with dual effects on telomere modification and immune activation. Full article
(This article belongs to the Special Issue Novel Molecules for Cancer Treatment (3rd Edition))
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Figure 1

Figure 1
<p>Biologic activity of phosphatidyl nucleoside conjugates in different human and murine cancer cell lines. General chemical structure of nucleoside phosphatidyl diglycerides, where R′ = H, and R″ = C3–C17 fatty acid residues; for diC6-THIOmolecule, R′ = H, R″ = C5 (<b>Aa</b>). Chemical structures of 6-thio-dG (<b>Ab</b>). Cell viability of human colorectal HT29 (<b>B</b>), human cervical HeLa (<b>C</b>), human NSCLC A549 (<b>D</b>), murine colorectal CT26 (<b>E</b>) cancer cell lines, and human dermal fibroblast HDFa cells (<b>F</b>) treated with the indicated concentrations of compounds for 4 days. Cell viability was measured using the MTT Assay. Samples were analyzed in triplicate, and EC<sub>50</sub> values were calculated using GraphPad Prism.</p> Full article ">Figure 2
<p>diC6-THIOinduces more TIFs compared to 6-thio-dG. Representative 2D images of TIF and DNA damage foci for diC6-THIO and 6-thio-dG in HT29 and CT26 cells with 1 μM treatment for 4 days. Green: Telomeric probe, red: gammaH2AX, yellow: TIFs, and blue: DAPI (<b>A</b>). Merged images with arrows show the representative pictures of TIFs (<b>A</b>); the quantitative measurements of TIF volumes (<b>B</b>); and global DNA damage (<b>C</b>) of HT29, HeLa, and CT26 cells treated with diC6-THIO (1 μM) and 6-thio-dG (1 μM) for 4 days. Data are shown as means ± SEM from two to three independent experiments. <span class="html-italic">p</span>-value was determined by two-way ANOVA followed by a post hoc test (Tukey’s). All TIF and global DNA damage volumes were scored by DiAna plugin (n ≈ 50 for HT29, HeLa, and CT26 cells. <span class="html-italic">p</span>-values for TIF between control vs. 6-thio-dG (**** <span class="html-italic">p</span> &lt; 0.0001) or control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001) or 6-thio-dG vs. diC6-THIO (* <span class="html-italic">p</span> = 0.0147) in HT29; control vs. 6-thio-dG (**** <span class="html-italic">p</span> &lt; 0.0001) or control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001) or 6-thio-dG vs. diC6-THIO (<span class="html-italic">p</span> = 0.9966) in HeLa; and control vs. 6-thio-dG (**** <span class="html-italic">p</span> &lt; 0.0001) or control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001) or 6-thio-dG vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001) in CT26. ns, not significant. <span class="html-italic">p</span>-values for global DNA damage between control vs. 6-thio-dG (**** <span class="html-italic">p</span> &lt; 0.0001) or control vs. diC6-THIO (*** <span class="html-italic">p</span> = 0.0001) or 6-thio-dG vs. diC6-THIO (<span class="html-italic">p</span> = 0.8267) in HT29; control vs. 6-thio-dG (*** <span class="html-italic">p</span> = 0.0004) or control vs. diC6-THIO (** <span class="html-italic">p</span> = 0.0014) or 6-thio-dG vs. diC6-THIO (<span class="html-italic">p</span> = 0.9314) in HeLa; and control vs. 6-thio-dG (** <span class="html-italic">p</span> = 0.0077) or control vs. diC6-THIO (*** <span class="html-italic">p</span> = 0.0003) or 6-thio-dG vs. diC6-THIO (<span class="html-italic">p</span> = 0.5879) in CT26. ns, not significant.</p> Full article ">Figure 3
<p>diC6-THIO reduces tumor growth in xenograft and syngeneic mouse models. Xenograft model with HT29 cells. The mice were subjected to 3 mg/kg diC6-THIO treatment (total of 6 doses on days 0, 2, 4, 6, 8, and 10, with day 0 designated as the day of treatment start) and 6 mg/kg diC6-THIO treatment (total of 4 doses on days 0, 2, 4, and 6, with day 0 designated as the day of treatment start). Tumor volumes were scored by GraphPad Prism (n = 2 per each group for nude CD1 mice, 2 × 10<sup>6</sup> HT29 cells were injected). *** <span class="html-italic">p</span> = 0.0003 (control vs. 3 mg/kg diC6-THIO), **** <span class="html-italic">p</span> &lt; 0.0001 (control vs. 6 mg/kg diC6-THIO), and *** <span class="html-italic">p</span> = 0.0008 (3 mg/kg diC6-THIO vs. 6 mg/kg) in two-way ANOVA, (control; untreated) (<b>A</b>). The BALB/c mice tumor volume measurements. 2 × 10<sup>6</sup> murine CT26 cells were injected. BALB/c mice bearing CT26 tumors were treated with diC6-THIO (3 mg/kg, days 0, 2, 7, and 9, with day 0 designated as the day of treatment start). Data are shown as means ± SEM from two independent experiments. <span class="html-italic">p</span>-value was determined by two-way ANOVA by using GraphPad Prism. (n = 10 per each group, **** <span class="html-italic">p</span> &lt; 0.0001 control vs. diC6-THIO in two-way ANOVA, control; untreated) (<b>B</b>). Individual tumor growth of control and diC6-THIO treatment groups (<b>C</b>). Graph shows body weight changes of mice in percentage following diC6-THIO treatment. The weights were measured every 2 days (<b>D</b>).</p> Full article ">Figure 4
<p>Therapeutic efficacy of diC6-THIO when sequentially combined with anti-PD-1 and anti-PD-L1 in MC38 and CT26 colon cancer models. Data are shown as means ± SEM. <span class="html-italic">p</span>-value was determined by two-way ANOVA by using GraphPad Prism. In MC38 mouse model treatment groups, the mice were administered with 6 mg/kg diC6-THIO (i.v.) or 6 mg/kg sdiC6-THIO (i.v.) on days 0, 1, 2, 7, 8, and 9 and/or 10 mg/kg anti-PD-1 (i.p.) on days 4 and 12 (n = 8 per group). There were statistically significant differences between control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001), control vs. diC6-THIO + anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), diC6-THIO + anti-PD-1 vs. anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), control vs. diC6-THIO + anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), anti-PD-1 vs. DIC6-THIO + anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), diC6-THIO vs. diC6-THIO + anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), sdiC6-THIO vs. sdiC6-THIO + anti-PD-1 (** <span class="html-italic">p</span> = 0.0013), and diC6-THIO vs. sdiC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001). No significant differences (ns) were found between control vs. sdiC6-THIO (<span class="html-italic">p</span> = 0.9301), control vs. anti-PD-1 (<span class="html-italic">p</span> = 0.1357), control vs. sdiC6-THIO + anti-PD-1 (<span class="html-italic">p</span> = 0.0756), and anti-PD-1 vs. sdiC6-THIO + anti-PD-1 (<span class="html-italic">p</span> = 0.9995). For statistical calculations, the final measurements from the euthanized mice are included until the completion of each group, which is determined by the endpoint reached when all mice in that group die. When comparing two groups, the statistical calculations consider the endpoint of the earlier group as reference (<b>A</b>). The body weight changes in percentage from MC38 control, diC6-THIO, sdiC6-THIO, diC6-THIO+ anti-PD-1, sdiC6-THIO + anti-PD-1, and anti-PD-1 groups (<b>B</b>). Individual MC38 tumor growth curves from control and treatment groups (<b>C</b>). In the CT26 mouse model, the mice were administered with 3 mg/kg diC6-THIO (i.p.) on days 0, 2, 7, 9 and/or 10 mg/kg anti-PD-L1 (i.p.) on days 4, 11. there was statistically significant difference between control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001), control vs. diC6-THIO + anti-PD-L1 (**** <span class="html-italic">p</span> &lt; 0.0001), diC6-THIO vs. anti-PD-L1 (*** <span class="html-italic">p</span> = 0.0009), and diC6-THIO + anti-PD-L1 vs. anti-PD-L1 (*** <span class="html-italic">p</span> = 0.0003). No significant differences were found between diC6-THIO vs. diC6-THIO + anti-PD-L1 (<span class="html-italic">p</span> = 0.3222) and control vs. anti-PD-L1 (<span class="html-italic">p</span> = 0.4222). For statistical purposes only, the final measurements from the euthanized mice were included up to the completion of each group, which occurred on day 19 (<b>D</b>). The body weight changes of mice in percentage from CT26 control, diC6-THIO, diC6-THIO + anti-PD-L1, and anti-PD-L1 groups (<b>E</b>). Individual CT26 tumor growth curves from control and treatment groups (<b>F</b>).</p> Full article ">Figure 5
<p>Immunophenotyping of CT26 bearing mice after diC6-THIO treatment. Total leukocyte (<b>A</b>) subpopulations. Myeloid subpopulations (<b>B</b>–<b>D</b>), lymphocyte subpopulations (<b>E</b>–<b>I</b>), and cytotoxic T cells/T regulatory cells ratio (<b>J</b>) in tumor tissue (number of cells in tumor tissue(#)/mg). Data are shown as means ± SEM. <span class="html-italic">p</span>-values were determined by unpaired Student’s <span class="html-italic">t</span>-test by using GraphPad Prism. Despite the lack of statistical significance among the groups for CD8<sup>+</sup>, CD8<sup>+</sup> CD62L<sup>−</sup>, CD8<sup>+</sup> CD4<sup>+</sup> FoxP3<sup>+</sup>, and CD4<sup>+</sup> FoxP3<sup>+</sup> panels (<span class="html-italic">p</span> &gt; 0.05), the trend for T helper and cytotoxic T cells were indicated that diC6-THIO has potential to induce activated T cell infiltration (<b>E</b>,<b>F</b>,<b>H</b>,<b>I</b>). Opposite, in the treatment group, T regulatory cell numbers decreased (<b>G</b>). Following diC6-THIO treatment cytotoxic T cells: T regulatory cells ratio increased (<b>J</b>).</p> Full article ">
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