Natural product-derived therapy for gynecologic cancers: A therapeutic mix encompassing Berberine (BER), Dihydroartemisinin (DHA), and Curcumin (CUR)inhibits the expression of HDAC6, acetylates tumor suppressor proteins, activates tumor suppressor function, and stifles the progression of ARID1A-mutated ovarian cancers via up-regulation of its target gene, 26/August/2017, 11.59 pm
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Introduction: What they say:
A study from Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA shows that “ARID1A-mutated ovarian cancers depend on HDAC6 activity” This study was published, in the 24 July 2017 issue of the journal “Nature Cell biology” [One of the best journals in Cell Biology with an I.F of 20.006 plus], by Prof.Zhang, Bitler BG, and others.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Natural product-derived therapy for gynecologic cancers: A therapeutic mix encompassing Berberine (BER), Dihydroartemisinin (DHA), and Curcumin (CUR)inhibits the expression of HDAC6, acetylates tumor suppressor proteins, activates tumor suppressor function, and stifles the progression of ARID1A-mutated ovarian cancers via up-regulation 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 due to lack of curative treatment available; (ii) cancer deaths globally are expected to be doubled by 2030; (iii) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide; (iv) Ovarian cancer not only one among the most common women cancers, but also the one of the most common invasive cancers in women; (v) Ovarian cancer not only metastasizes frequently, but also relapses; (vi) there is an increased incidence of ovarian cancer, as it has caused 113,000 deaths in 1990, while in 2010 160,000 deaths; (vii) it is the fifth leading cause of cancer death in women; (vii) in 2008, cancers of female reproductive organs has caused economic loss of 88 billion US dollars worldwide; and (ix) cancer 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) a cheaper alternative to the existing expensive anticancer drugs; (iii) a side-effect-free natural product-based drug; and (iv) a way to effectively treat and prevent metastatic progression and relapse of cancers.
What we infer from what they say:
The epigenetic regulator ARIDIA (Mutations in AT rich interactive domain 1A)/BAF250A has been shown to be frequently mutated in all human cancers. In particular, it is mutated in 50% of ovarian clear cell carcinomas. However, the molecular components that function downstream of ARID1A is far from understood.
Prof.Zhang’s research team has recently shown that: (1) HDAC6 is overexpressed in ARID1A-mutated ovarian cancers; (2) downregulation of HDAC6 in ARID1A-mutated ovarian cancers promotes survival of mice; (3) ARID1A transcriptionally represses the expression of HDAC6; (4) HDAC6 deacetylates Lys120 of tumor suppressor p53 and thereby inhibits its function; and (5) ARID1A mutation in cancer cells results in activation of HDAC6 and inactivation of p53 function, suggesting that inhibition of HDAC6 may promote apoptosis selectively in ARID1A-mutated cancers by increasing the expression of tumor suppressor p53 and its homologous proteins.
From research findings to therapeutic opportunity :
This study suggests a natural product-derived anticancer therapy for ARID1A-mutated cancers, including Clear cell ovarian cancers . Berberine (BER), Dihydroartemisinin (DHA), and Curcumin (CUR) have been shown to function as anticancer agents (fig. 1). However, the detailed mechanistic insights is yet to emerge.
A therapeutic mix encompassing Berberine (BER), Dihydroartemisinin (DHA), and Curcumin (CUR) [BDC], by increasing the expression of its target genes, it may inhibit the expression of HDAC6 (fig. 1). Thereby, it may: (i) acetylate tumor suppressor proteins; (ii) activate tumor suppressor proteins in ARID1A-mutated ovarian cancers; (iii) inhibit ovarian cancer progression; and (iv) promote survival (fig.1). Thus, pharmacological formulations encompassing “Berberine (BER), Dihydroartemisinin (DHA), and Curcumin (CUR) [BDC] or their analogues, either alone or in combination with other known anticancer drugs” may be used to inhibit the the progression of ARID1A-mutated ovarian cancers (fig. 2)
Figure 1. Mechanistic insights into how a therapeutic mix encompassing Berberine BER), Dihydroartemisinin (DHA), and Curcumin (CUR) [BDC] functions as an anticancer agent in ARID1A-mutated ovarian cancers.
Figure 2. A therapeutic mix encompassing natural product-derived compounds, such as Berberine BER), Dihydroartemisinin (DHA), and Curcumin (CUR) [BDC], may stall the progression of ARID1A-mutated ovarian cancers.
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 Berberine (BER), Dihydroartemisinin (DHA), and Curcumin (CUR) [BDC] decrease the expression of HDAC6 to stall the progression of ARID1A-mutated ovarian cancers?
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References:
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Citation: Boominathan, L., Natural product-derived therapy for gynecologic cancers: A therapeutic mix encompassing Berberine (BER), Dihydroartemisinin (DHA), and Curcumin (CUR)inhibits the expression of HDAC6, acetylates tumor suppressor proteins, activates tumor suppressor function, and stifles the progression of ARID1A-mutated ovarian cancers via up-regulation of its target gene, 26/August/2017, 11.59 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org
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