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G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy.

ABSTRACT: Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents is their strong toxicity and other side effects due to their poor selectivity. Uncontrolled proliferation of cancer cells is due to mutations, deletions, or amplifications in genes (oncogenes) encoding for proteins that regulate cell growth and division, such as transcription factors, for example, c-MYC. The direct targeting of the c-MYC protein has been attempted but so far unsuccessfully, as it lacks a definite binding site for the modulators. Meanwhile, another approach has been explored since the discovery that G-quadruplex secondary DNA structures formed in the guanine-rich sequences of the c-MYC promoter region can downregulate the transcription of this oncogene. Here, we will overview the major achievements made in the last decades towards the discovery of a new class of anticancer drugs targeting G-quadruplexes in the c-MYC promoter of cancer cells.

SUBMITTER: Bahls B

PROVIDER: S-EPMC10046398 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy.

Bahls Bárbara B Aljnadi Israa M IM Emídio Rita R Mendes Eduarda E Paulo Alexandra A

Biomedicines 20230321 3

Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents is their strong toxicity and other side effects due to their poor selectivity. Uncontrolled proliferation of cancer cells is due to mutations, deletions, or amplifications in genes (oncogenes) encoding for proteins that regulate cell growth and division, such as transcription factors, for example, <i>c-MYC</i>. The direct targeting of the c-MYC protein has been attempted but ...[more]

PMID: 36979947

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Project description:Prostate cancer (PCa) is the second leading cause of cancer-related death in American men and many PCa patients develop skeletal metastasis. Current treatment modalities for metastatic PCa are mostly palliative with poor prognosis. Epidemiological studies indicated that patients receiving the diabetic drug metformin have lower PCa risk and better prognosis, suggesting that metformin may have antineoplastic effects. The mechanism by which metformin acts as chemopreventive agent to impede PCa initiation and progression is unknown. The amplification of c-MYC oncogene plays a key role in early prostate epithelia cell transformation and PCa growth. The purpose of this study is to investigate the effect of metformin on c-myc expression and PCa progression. Our results demonstrated that (i) in Hi-Myc mice that display murine prostate neoplasia and highly resemble the progression of human prostate tumors, metformin attenuated the development of prostate intraepithelial neoplasia (PIN, the precancerous lesion of prostate) and PCa lesions. (ii) Metformin reduced c-myc protein levels in vivo and in vitro. In Myc-CaP mouse PCa cells, metformin decreased c-myc protein levels by at least 50%. (iii) Metformin selectively inhibited the growth of PCa cells by stimulating cell cycle arrest and apoptosis without affecting the growth of normal prostatic epithelial cells (RWPE-1). (iv) Reduced PIN formation by metformin was associated with reduced levels of androgen receptor and proliferation marker Ki-67 in Hi-Myc mouse prostate glands. Our novel findings suggest that by downregulating c-myc, metformin can act as a chemopreventive agent to restrict prostatic neoplasia initiation and transformation.Metformin, an old antidiabetes drug, may inhibit prostate intraepithelial neoplasia transforming to cancer lesion via reducing c-MYC, an 'old' overexpressed oncogene. This study explores chemopreventive efficacy of metformin in prostate cancer and its link to cMYC in vitro and in vivo.

Project description:BackgroundCancer remains an awful challenge, despite years of targeting proteins to control its relentless growth and spread. Fungal metabolites, a treasure of natural chemicals, offer a glimmer of hope. Telomeres, the cellular "caps," are a focal point in cancer research. This study explores the potential of stabilizing Telomeric Repeats-containing RNA G-quadruplex (TERRA G4) structures within telomeres. This stabilization could block telomerase, the enzyme that repairs telomeres, and potentially trigger cancer cell death. Agonodepsides A and B, two promising fungal metabolites, were chosen to investigate this exciting possibility.MethodsAgonodepside A and B were initially screened for drug likeness employing SwissAdme. AutoDock Vina was used for molecular docking, and ligands and TERRA G4 were prepared using PyRx and MGL tool. Discovery Studio software was utilized for the visualization of interactions between ligands and TERRA G4. For validation of docking results MD simulation for control and complexes was carried out for 250 ns and trajectories were analyzed for different parameters. MMPBSA was used to calculate binding free energy for control and complexes. To find the stable and lower energy states of complexes in comparison to control principal component analysis (PCA) and free energy landscape (FEL) were conducted.ResultsAbsorption, distribution, metabolism, and excretion (ADME) of both agonodepsides followed Lipinski's rule of five with zero violation. Molecular docking revealed several key interactions including hydrogen bonds, van der Waals interactions, π-alkyl and π-anion. MD simulation revealed that Agonodepside A interact with TERRA G4 and stabilize it while Agonodepside B interactions were transient. The MMPBSA binding free energy calculation, PCA and free energy landscapes supported the docking and MD simulation results.ConclusionLichenized fungi produce agonodepsides A and B, may fight cancer by targeting telomeres. Agonodepside A binds more strongly to telomeres than B, potentially blocking enzyme telomerase. Further studies are required to validate these findings and evaluate potential safety concerns.

Dataset Information

G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy.

Publications

G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy.

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