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Natural product-based therapy for CyclinD3-CDK6 overexpressing cancers: Nimbolide, isolated from Azadirachta indica, inhibits the activity of glycolytic enzymes 6-phosphofructokinase and pyruvate kinase M2, decreases antioxidants NADPH and glutathione levels, increases reactive oxygen species levels, promotes apoptosis, and inhibits the progression of CyclinD3-CDK6 overexpressing cancers via down regulation of its target gene, 10/April/2018, 6.41 pm

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Introduction: What they say

A study from Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA shows that “The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival.” This research paper was published, in the 15 June 2017 issue of the journal “Nature” [One of the best research journals in Biology with an I.F of 43+], by Prof.Piotr Sicinski, Haizhen Wang, 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-based therapy for CyclinD3-CDK6 overexpressing cancers: Nimbolide, isolated from Azadirachta indica, inhibits the activity of glycolytic enzymes 6-phosphofructokinase and pyruvate kinase M2, decreases antioxidants NADPH and glutathione levels, increases reactive oxygen species levels, promotes apoptosis, and inhibits the progression of CyclinD3-CDK6 overexpressing cancers via down regulation of its target gene


Significance of the study:

Given that: (1) the drivers of the cell cycle, the cyclins and their activating partners, Cyclin-dependent kinases, are often overexpressed in a number of cancers; (2) our understanding is incomplete in terms of downstream molecular targets and the oncogenic/malignant pathways involved in CyclinD3-CDK6-overexpressing cancers; (3) even intense multimodal treatment saves only an insignificant number of metastatic cancer patients; and (4) cancer causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (i) a cheaper alternative to the existing expensive drugs; (ii) a side-effect-free natural product-based drug; (iii) a target specific anti-cancer drug, with a detailed mechanism of action; (iv) a way to effectively treat and stall metastatic progression and relapse of Cyclin D3-CDK6-overexpressing cancers.


What is known?

A number of studies suggests that D-type cyclins and their associated cyclin-dependent kinases are frequently overexpressed in a number of cancer cells.

Prof. Piotr Sicinski’s research team has recently shown that: (1) cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of glycolytic enzymes, such as 6-phosphofructokinase(6-PFK) and pyruvate kinase M2 (PKM2); (2) inhibition of 6-PFK and PKM2 results in redirection of glycolytic pathway intermediates into the pentose phosphate (PPP) and serine pathways; (3) suppression of cyclin D3-CDK6 kinase results in (i) depletion of antioxidants such as NADPH and glutathione; (ii) increased levels of reactive oxygen species; and (iii) apoptosis of cancer cells; (4) inhibition of cyclin D3-CDK6 complexes in cancer cells expressing higher levels of them undergo apoptosis and tumor regression, while normal cells expressing lower levels of them undergo cell cycle arrest, suggesting that tumors that contain higher levels of cyclin D3-CDK6 complexes may be pharmacologically targeted for cancer therapy.


From research findings to therapeutic opportunity:

This study suggests, for the first time, a natural product based therapy for cyclinD3-CDK6 overexpressing cancers. Nimbolide, by increasing the expression of its target genes, it may decrease the expression of Cyclin D3 and CDK6. Thereby, it may: (1) decrease the expression of glycolytic enzymes, such as 6-phosphofructokinase(6-PFK) and pyruvate kinase M2 (PKM2); (2) lower antioxidants NADPH and glutathione; (3) augment reactive oxygen species; (4) induce DNA damage; and (5) promote apoptosis in cancer cells.

Figure 1. Mechanistic insights into how Nimbolide inhibits the progression of tumors that contain higher levels of cyclin D3-CDK6 complexes.

Figure 2. The chemical structure of Nimbolide. Nimbolide functions as an anticancer agent through downregulation of 6-PFK and PKM2.

Thus, pharmacological formulations encompassing “Nimbolide or its analogues, either alone or in combination with other drugs,” may be used to treat tumors that are enriched with cyclin D3-CDK6 complexes.

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Details of the research findings:

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

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Undisclosed mechanistic information: How Nimbolide inhibits the expression of cyclinD3-CDK6, 6-PFK and PKM2 and stalls the progression of cancers

Amount: $100#

# Research cooperation


References:

Citation: Boominathan, L., Natural product-based therapy for CyclinD3-CDK6 overexpressing cancers: Nimbolide, isolated from Azadirachta indica, inhibits the activity of glycolytic enzymes 6-phosphofructokinase and pyruvate kinase M2, decreases antioxidants NADPH and glutathione levels, increases reactive oxygen species levels, promotes apoptosis, and inhibits the progression of CyclinD3-CDK6 overexpressing cancers via down regulation of its target gene, 10/April/2018, 6.41 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

Web: http://genomediscovery.org or http://newbioideas.com

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