Combinatorial  therapy for human cancers: A pharmaceutical mixture encompassing Radicicol, 5′-Aza-2′-deoxycytidine (5-Aza-dC), Andrographlide (ANDRO), Metformin, Berberine, Salinomycin, Fluoxetine, Curcumin, Calcitriol, Pravastatin (RAAMBSFCCR) inhibits the expression of KAT6A and KAT6B, increases the expression of INK4a/ARF and other genes, promotes senescence, prevents cancer recurrence, and prolongs survival, via up-regulation of its target gene, 16/September/2018, 10.55  pm

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Introduction: What they say:

A study from the Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia; and Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia shows that “Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.” This study was published, in the 1 August 2018 issue of the journal “Nature” [One of the best journals in “General science” with an I.F of 43 plus], by Profs. Jonathan B Baell and Thomas 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 human cancers: A pharmaceutical mixture encompassing Radicicol, 5′-Aza-2′-deoxycytidine (5-Aza-dC), Andrographlide (ANDRO), Metformin, Berberine, Salinomycin, Fluoxetine, CurcuminCalcitriolPravastatin (RAAMBSFCCR) inhibits the expression of KAT6A and KAT6B, increases the expression of INK4a/ARF and other genes, promotes senescence, prevents cancer recurrence, and prolongs survival, via up-regulation of its target gene


The 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; and (iv) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find/activate: (i) patients’ immune system against tumors (Cancer immunotherapy); (ii) anti-cancer drugs that target cancer stem cells, as they may aid in preventing tumor relapse and resistance; (iii) anti-cancer drugs that target cell adhesion molecules, as they aid in preventing metastatic spread; (iv) a cheaper alternative to the existing expensive anticancer drugs; (v) a side-effect-free natural product-based drug (as both chemotherapy and radiotherapy damage DNA and cause a number of side effects); (vi) senescence mechanisms–as they do not damage DNA, but make cancer cells exit cell cycle permananetly, and thereby keep them in the arrested state–in cancer cells; (vii) a way to increase the therapeutic index of anti-cancer drugs; and (viii) a way to effectively treat and prevent metastatic progression and relapse and recurrence of advanced/drug-resistant cancers.


What we infer from what they say:

KAT6A and KAT6B have been shown to acetylate histones and thereby function as lysine acetyltransferases. Interestingly, KAT6A is one among the top 12 genes amplified in human cancers.

Prof. Jonathan B Baell’s research team has recently identified inhibitors of KAT6A and KAT6B that: (1) promote cell cycle exit, and cellular senescence, without excessive cellular DNA damage; (2) promote senescence through activation of INK4a/ARF pathway; and (3) promote senescence in a zebrafish, and mouse model of hepatocellular carcinoma, and lymphoma, respectively, suggesting that suppressing the expression of KAT6A and KAT6B, that regulate histone acetylation, may activate senescence mechanisms in cancer cells and stall their progression.


From research findings to therapeutic opportunity :

This study suggests, for the first time,  a natural product-derived combinatorial therapy for senescence induction in cancer cells. A therapeutic mix encompassing Radicicol, 5′-Aza-2′-deoxycytidine (5-Aza-dC), Andrographlide (ANDRO), Metformin, Berberine, Salinomycin, Fluoxetine, CurcuminCalcitriolPravastatin (RAAMBSFCCR), by increasing the expression of its target genes, it may decrease the expression proteins that regulate histone acetylation, such as KAT6A and KAT6B (fig. 1). Thereby, it may: (i) increase the expression of genes, such as INK4a/ARF and others, that promote senescence; (2) suppress the expression of EMT(epithelial to mesenchymal transition) protein Zeb1; (3) increase the expression of a number of tumor suppressor genes; (4) dismantle oncogenic/pro-invasive/migration/metastatic gene network; (5) increase chemotherapeutic response; (6) inhibit tumor cell growth and metastasis; (7) inhibit tumor relapse and recurrence; and (8) promote survival. Thus, pharmacological formulations encompassing “Radicicol, 5′-Aza-2′-deoxycytidine (5-Aza-dC), Andrographlide (ANDRO), Metformin, Berberine, Salinomycin, Fluoxetine, CurcuminCalcitriolPravastatin (RAAMBSFCCRor their analogs, either alone or in combination with other known anticancer drugs,” may be used to inhibit therapy-resistant recurrent human cancers. Given the mechanistic basis of how RAAMBSFCCR may function as a potent anti-cancer/metastatic agent, for the wide-range of tumors, oncologists and general practitioners may consider a starting a clinical trial (to ascertain the clinical utility of the finding presented here).  Finally, depending on the stage of the tumor, level of toxicity, genetic mutations, the molecular signature of tumors, and the side effects, the composition of the anti-cancer/metastatic drug RAAMBSFCCR can be altered. For instance, non-metastatic tumors or tumors that are in the initial stages, a therapeutic mix encompassing  Metformin, Berberine, Calcitriol, and Curcumin (MBCC) can be tried first to check how tumors respond.

Figure 1. Mechanistic insights into how a therapeutic mix encompassing Radicicol, 5′-Aza-2′-deoxycytidine (5-Aza-dC), Andrographlide (ANDRO), Metformin, Berberine, Salinomycin, Fluoxetine, CurcuminCalcitriolPravastatin (RAAMBSFCCR) suppress the expression of oncogenic KAT6A and KAT6B and increases the expression of tumor-suppressive INK4a/ARF.

Figure 2. The chemical structure of Radicicol, 5′-Aza-2′-deoxycytidine (5-Aza-dC), Andrographlide (ANDRO), Metformin, Berberine, Salinomycin, Fluoxetine, Curcumin, Calcitriol, Pravastatin (RAAMBSFCCR).

Figure 3. RAAMBSFCCR activates the senescence mechanism in cancer cells and stalls cancer progression

 

 

 

 

 

 


Details of the Research findings:

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

Amount: $1, 500#

Undisclosed mechanistic information: How does a therapeutic mix encompassing Radicicol, 5′-Aza-2′-deoxycytidine (5-Aza-dC), Andrographlide (ANDRO), Metformin, Berberine, Salinomycin, Fluoxetine, CurcuminCalcitriolPravastatin (RAAMBSFCCR)  decrease the expression of oncogenic KAT6A and KAT6B?

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References:

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Citation: Boominathan, L., Combinatorial  therapy for human cancers: A pharmaceutical mixture encompassing Radicicol, 5′-Aza-2′-deoxycytidine (5-Aza-dC), Andrographlide (ANDRO), Metformin, Berberine, Salinomycin, Fluoxetine, CurcuminCalcitriolPravastatin (RAAMBSFCCR) inhibits the expression of KAT6A and KAT6B, increases the expression of INK4a/ARF and other genes, promotes senescence, prevents cancer recurrence, and prolongs survival, via up-regulation of its target gene, 16/September/2018, 10.55  pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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