Combinatorial therapy for prostate cancer bone metastasis:  A pharmaceutical mixture encompassing Metformin and Navitoclax (MAN) inhibits the expression of Monoamine oxidase A (MAOA), inhibits Shh-IL6-RANKL signaling network, suppresses tumor-stromal interactions, reduces prostate cancer metastasis and prolongs survival via upregulation of its target gene, 15/February/2019, 6.21 am

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Introduction: What they say:

A study from the Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA shows that “MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions.” This study was published, in the 13 March 2017 issue of the journal “Cancer Cell” [One of the best journals in Cancer Biology with an I.F of 23.523], by Profs. Jason Boyang Wu, Leland W.K. Chung, 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 prostate cancer bone metastasis:  A pharmaceutical mixture encompassing Metformin and Navitoclax (MAN) inhibits the expression of Monoamine oxidase A (MAOA), inhibits Shh-IL6-RANKL signaling network, suppresses tumor-stromal interactions, reduces prostate cancer metastasis and prolongs survival via upregulation of its target gene

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Price 300


From Significance of the study to Public health relevance:

Given that: (i) prostate cancer is one of the most common form of disease in men; and about 1 in 8 will get it in their lifetime; (ii) each year nearly 14 million people are diagnosed with cancer globally; (iii) each year 176,000 cases of prostate cancer are identified in the US, and about 16% of them will die, while in the UK each year 47,000 cases are identified, and about one fourth of them will die; (iv) about 70% of Prostate cancers are deficient in tumor suppressor gene PTEN, the second most mutated gene in human cancer, the first being tumor suppressor Tp53; (v) cancer deaths globally are expected to be doubled in the next decade; (vi) metastasis is the principal reason for most of the cancer deaths; (vii) 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 activate patients’ immune system against tumors (Cancer immunotherapy); (ii) anticancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iii) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (iv) a cheaper alternative to the existing expensive anticancer drugs; (v) a side-effect-free natural product-based drug; (vi) increase the therapeutic index of anti-cancer drugs; and (vii) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What we infer from what they say:

Prof. Wu’s research team has recently shown that: (1) Monoamine oxidase A (MAOA) activates the paracrine Shh-IL6-RANKL signaling; (2) MAOA promotes Prostate cancer bone and visceral metastases; (3) MAOA promotes tumor-stromal cell interactions; and (4) inhibition of MAOA, using antidepressant drug clorgyline, dismantles Shh-IL6-RANKL signaling network and reduces metastasis.


From research findings to therapeutic opportunity :

This study suggests a natural product-derived therapy for prostate cancer metastasis.

A therapeutic mix encompassing Metformin and Navitoclax (MAN)by increasing the expression of its target genes, it may decrease the expression of MAOA (fig. 1). Thereby, it may: (i) inhibit paracrine Shh signaling in tumor-stromal interactions; (ii) inhibit secretion of Receptor activator of nuclear factor kappa-B ligand (RANKL) and Interleukin-6 (IL6) by bone-forming cells; (iii) inhibit skeletal colonization and osteoclastogenesis; (iv) dismantle Shh-IL6-RANKL signaling network; (v) inhibit tumor growth in the tumor microenvironment; (vi) reduce bone metastasis; and (vii) promote survival.

Figure 1. Mechanistic insights into how a therapeutic mix encompassing Metformin and Navitoclax (MAN) suppresses the expression of MAOA and stalls prostate cancer bone metastasis.

Figure 2. Combinatorial therapy for Prostate cancer.

Thus, pharmacological formulations encompassing “Metformin and Navitoclax (MAN) or their analogs, either alone or in combination with other known anticancer drugs, ” may be used to inhibit prostate cancer bone metastasis.


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 (MAN) decrease the expression of MAOA to promote metastatic prostate cancer regression?

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References:

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Citation: Boominathan, L., Combinatorial therapy for prostate cancer bone metastasis: A pharmaceutical mixture encompassing Metformin and Navitoclax (MAN) inhibits the expression of Monoamine oxidase A (MAOA), inhibits Shh-IL6-RANKL signaling network, suppresses tumor-stromal interactions, reduces prostate cancer metastasis and prolongs survival via upregulation of its target gene, 15/February/2019, 6.21 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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