Combinatorial therapy for drug-resistant cancers: A therapeutic mix encompassing Metformin and Navitoclax (ABT-263) (MAN) inhibits the expression of phospholipid glutathione peroxidase (GPX4), inhibits GPX4 signaling network and lipid peroxidase pathway, suppresses EMT protein ZEB1, increases sensitivity to anticancer therapy and prolongs survival via upregulation of its target gene, 3/February/2019, 10.58 pm

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Introduction: What they say:

A study from Broad Institute, Cambridge, Massachusetts, USA, Howard Hughes Medical Institute, Chevy Chase, Maryland and Department of Chemistry and Chemical Biology, Harvard University, Oxford St., Cambridge, Massachusetts, USA shows that “Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.” This study was published, in the 5 July 2017 issue of the journal “Nature” [One of the best journals in General Science with an I.F of 43 plus], by Prof. and the co-founder of Broad Institute Schreiber SL, Viswanathan VS and others, 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 drug-resistant cancers: A therapeutic mix encompassing Metformin and Navitoclax (ABT263) (MAN) inhibits the expression of phospholipid glutathione peroxidase (GPX4), inhibits GPX4 signaling network and lipid peroxidase pathway, suppresses EMT protein ZEB1, increases sensitivity to anticancer therapy and prolongs survival 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; (ii) cancer deaths globally are expected to be doubled in the next decade; (iii) metastasis is the principle reason for most of the cancer deaths; (iv) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (v) activate patients’ immune system against tumors (Cancer immunotherapy); (vi) anti-cancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (vii) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (viii) a cheaper alternative to the existing expensive anticancer drugs; (ix) a side-effect-free natural product-based drug; (x) increase the therapeutic index of anti-cancer drugs; and (xi) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What we infer from what they say:

A number of studies suggest that transition from one cell state to another promotes drug resistance to multiple classes of cancer therapies. The resistance to anti-cancer drug therapy limits their effectiveness. Furthermore, it has been reported that high mesenchymal cell state, which promotes resistance to anti-cancer drug therapy, is observed in a number of human cancers. However, the mechanistic basis of the therapy-resistant mesenchymal state is far from understood.

Prof.Schreiber’s research team has recently shown that:(1) a lipid-peroxidase pathway, that is responsible for the prevention of ferroptosis (a non-apoptotic form of cell death), is activated in a number of cancer cells; (2) phospholipid glutathione peroxidase (GPX4), that is responsible for dissipation of lipid peroxides that promote ferroptic cell death, is activated in epithelial-derived carcinomas, (TGFß-mediated therapy-resistance) melanoma, prostate cancer, and sarcomas; (3) tumors that depend on glutathione peroxidase (GPX4) are characterized by high expression of epithelial to mesenchymal transition (EMT) protein Zeb1; (4) inhibition of the lipid peroxidase pathway has made therapy-resistant cancer cells vulnerable to ferroptosis, suggesting that dismantling GPX4-signaling network in cancer cells characterized by therapy-resistant mesenchymal state, will make them sensitive to anti-cancer drug therapy.


From research findings to therapeutic opportunity :

This study suggests a natural product-derived therapy for drug-resistant prostate cancer metastasis.  Metformin and Navitoclax (ABT263) (MAN) have been shown to function as anticancer agents (fig. 1). However, the detailed mechanistic insights are yet to emerge.

A therapeutic mix encompassing Metformin and Navitoclax (ABT263) (MAN), by increasing the expression of its target genes, it may decrease the expression of upstream and downstream components of glutathione-dependent antioxidant enzyme GPX4 (fig. 1). Thereby, it may: (i) inhibit lipid-peroxidase pathway; (2) accumulate lipid peroxides; (3) increase ferroptosis; (4) suppress mesenchymal state in therapy-resistant cancers; (5) decrease the expression of EMT protein Zeb1; (6) increase the expression of a number of tumor suppressor genes;(iv) dismantle GPX4 signaling network; (7) inhibit tumor growth; (8) reduce metastasis; and (9) promote survival (Fig 2).

Figure 1. Mechanistic insights into how a therapeutic mix encompassing Metformin and Navitoclax (ABT263) (MAN) suppresses the expression of GPX4 to make therapy-resistant mesenchymal state sensitive to anti-cancer drug therapy

Figure 2. The chemical structure of Metformin and Navitoclax (ABT-263) (MAN)

Thus, pharmacological formulations encompassing Metformin and Navitoclax (ABT263) (MAN) or their analogs, either alone or in combination with other known anticancer drugs” may be used to inhibit therapy-resistant mesenchymal state-enriched human cancers.

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Details of the Research findings:

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

Amount: $500#

Undisclosed mechanistic information: How does a therapeutic mix encompassing Metformin and Navitoclax (ABT263) (MAN) decrease the expression of GPX4 to augment sensitivity of therapy-resistant cancer cells to anticancer therapy?

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References:

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Citation: Boominathan, L., Combinatorial therapy for drug-resistant cancers: A therapeutic mix encompassing Metformin and Navitoclax (ABT263) (MAN) inhibits the expression of phospholipid glutathione peroxidase (GPX4), inhibits GPX4 signaling network and lipid peroxidase pathway, suppresses EMT protein ZEB1, increases sensitivity to anticancer therapy and prolongs survival via upregulation of its target gene, 3/February/2019, 10.58 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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