Combinatorial therapy for metastatic prostate cancer: A therapeutic mix encompassing Metformin and Navitoclax/ABT-263 (MAN) inhibits the expression of CDC42, CDC42EP3, RAC1 and ARPC5, and GAS6, suppresses the expression of stem cell molecules CD44 and EZH2, promotes epithelial phenotype, suppresses tumorigenesis, migration, invasion, stem cell regeneration and metastasis via upregulation of its target gene, 9/February/2018, 6.53 am

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Introduction: What they say:

A study from the Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park, Texas 78957, USA shows that “MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes.” This study was published, in the 23 January 2017 issue of the journal “Nature communications”

, by Prof. G Dean Tan, Liu C, and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  Combinatorial therapy for metastatic prostate cancer: A therapeutic mix encompassing Metformin and Navitoclax/ABT-263 (MAN) inhibits the expression of CDC42, CDC42EP3, RAC1 and ARPC5, and GAS6, suppresses the expression of stem cell molecules CD44 and EZH2, promotes epithelial phenotype, suppresses tumorigenesis, migration, invasion, stem cell regeneration and metastasis via upregulation of its target gene


From Significance of the study to Public health relevance:

Given that: (i) each year nearly 14 million people are diagnosed with cancer globally, and little more than half of them will die; (ii) each year 176,000 cases of prostate cancer are identified in the US; and about 28,000 of them will die; (iii) about 70% of Prostate cancers are deficient in tumor suppressor gene PTEN, the second most mutated gene in cancer, next to tumor suppressor Tp53; (iv) cancer deaths globally are expected to be doubled by 2030; (v) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (i) a way to prevent an individual from being susceptible to cancer by strengthening his/her own immune system (Cancer immunotherapy); (ii) anticancer drugs that inhibit cancer stem cells that aid in tumour relapse and drug resistance; (iii) a cheaper alternative to the existing expensive anticancer drugs; (iv) a side-effect-free natural product-based drug; (v) increase the therapeutic index of anti-cancer drugs; and (vi) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What we infer from what they say:

Prof. Dean Tan’s research team has recently shown that overexpression of MiR-141: (1) promotes strong epithelial phenotype; (2) promotes a partial loss of mesenchymal phenotype; (3) suppresses the expression of Rho GTPase family members, including CDC42, CDC42EP3, RAC1, ARPC5 and Gas6; (4) inhibits the expression of stem cell molecules such as CD44/Pgp-1 and EZH2; (5) inhibits cancer stem cell properties including holoclone and sphere formation; and (6) inhibits invasion, migration, tumour stem cell regeneration and metastasis.


From research findings to therapeutic opportunity :

This study suggests a combinatorial-therapy for prostate cancer metastasis.  Both Metformin and Navitoclax/ABT-263 (MAN) have been shown to function as anticancer agents (fig. 1). However, detailed mechanistic insights are yet to emerge.

A therapeutic mix encompassing Metformin and Navitoclax/ABT-263 (MAN), by increasing the expression of its target genes, it may increase the expression of MiR-141, while decreasing the expression of CDC42, CDC42EP3, RAC1, ARPC5 and Gas6 (fig. 1). Thereby, it may: (i) decrease the expression of stem cell molecules such as CD44/Pgp-1 and EZH2; (ii) enforce strong epithelial phenotype on poorly differentiated cancer cells; (iii) inhibit cancer stem cell properties; (iv) suppress tumour stem cell regeneration; and (v) inhibit invasion, migration and metastasis.

Figure 1. Mechanistic insights into how a therapeutic mix encompassing Metformin and Navitoclax/ABT-263 (MAN)  suppresses the expression of CDC42, CDC42EP3, RAC1, ARPC5, Gas6, CD44/Pgp-1 and EZH2 and inhibits prostate cancer metastasis

Figure 2. Combinatorial therapy for metastatic prostate cancer.

Thus, pharmacological formulations encompassing “Metformin and Navitoclax/ABT-263 (MAN)  or their analogues, either alone or in combination with other known anticancer drugs,” may be used to inhibit metastatic progression and stem cells properties of prostate cancers.[easy_payment currency=”USD”]

Given the inexpensive nature, compared to other anticancer drugs in the market, and mechanistic insights as to how MAN may function as a potent anti-cancer/metastatic agent, oncologists, and general practitioners may consider: treating their cancer patients with it or beginning a clinical trial. 


Details of the Research findings:

Idea Proposed/Formulated (with experimental evidence) by Dr L Boominathan Ph.D.

Amount: $300#

Undisclosed mechanistic information: How does a therapeutic mix encompassing Metformin and Navitoclax/ABT-263 (MAN)   decrease the expression of stem cell proteins to inhibit metastatic prostate cancer progression?

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References:

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Citation: Boominathan, L., Combinatorial therapy for metastatic prostate cancer: A therapeutic mix encompassing Metformin and Navitoclax/ABT-263 (MAN) inhibits the expression of CDC42, CDC42EP3, RAC1 and ARPC5, and GAS6, suppresses the expression of stem cell molecules CD44 and EZH2, promotes epithelial phenotype, suppresses tumorigenesis, migration, invasion, stem cell regeneration and metastasis via upregulation of its target gene, 9/February/2018, 6.53 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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