Natural product-derived therapy for triple-negative breast tumors: Cucurbitacin D, found in Trichosanthes kirilowii (Gualou), Phormium tenax, and Luffa amara among others, increases the levels of cell cycle inhibitor, p27, inhibits pro-survival pathways mediated by c-Myc, and inhibits the progression of triple-negative breast cancer via up-regulation of its target gene, 10/December/2016, 7.21 pm

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Introduction: What they say

A study from the Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA shows thatPIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression”

Another study, carried out in parallel, from the Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King’s College London, Guy’s Hospital, London, UK and Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK. shows that “PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer”

These research papers were published in the 24 October 2016 issue of the journal “Nature Medicine” [the number 1 research journal in General Medicine with an I.F of 30.357+] by Profs. Andrei Goga’s (USA) and Andrew N Tutt’s (UK) research teams.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Natural product Withaferin A increases the levels of cell cycle inhibitor, p27, inhibits pro-survival pathways mediated by c-Myc, and inhibits the progression of triple-negative breast cancer via up-regulation of its target gene


From Significance of the study to Public health relevance:

Given that: (1) Breast cancer not only the most common women cancer, but also the most common invasive cancer in women; (2) Breast cancer not only metastasizes frequently, but also relapses; (3) Out of the all the known breast cancer subtypes, triple-negative–for estrogen receptor, the progesterone receptor and the HER2 receptor–breast cancers is one of the hardest to treat, as we lack details of molecular targets and the oncogenic/malignant pathways involved; (4) in 2008, breast cancer has caused more than 400000 deaths; and it is the second leading cause of cancer death in women; (5) in 2008, breast cancer has caused economic loss of 88 billion US dollars worldwide; (6) 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; and (iii) a way to effectively treat and stall metastatic progression and relapse of triple-negative drug-resistant breast cancer.


What is known?

Prof. Gaga’s research team has recently shown that triple-negative breast tumors: (1) contain increased levels of c-Myc; and (2) contain increased levels of PIM1 kinase. Further, they showed that inhibition of PIM1 kinase, in c-Myc over-expressing triple-negative breast tumors, not only regressed, but also stalled the progression triple-negative breast tumors, via induction of cell cycle inhibitor p27.

In parallel, Prof. Andrew N Tutt’s research team has shown that triple-negative breast cancers (TNBCs): (1) have high copy number and the expression of oncoprotein PIM1; (2) contain increased levels of pro-survival protein Bcl-2; and (2) contain increased levels of c-Myc and its target gene Mcl-1. Further, they showed that knockdown/ depletion of PIM1 in TNBC’s resulted in: (1) decreased expression of Bcl-2; and (2) increased chemosensitivity.


From Research findings to Therapeutic opportunity

This study suggests, for the first time, a natural product based therapy for triple-negative breast cancer. Cucurbitacin D, by decreasing the expression of its target gene, it may increase the expression of cell cycle inhibitor, p27. Thereby, it may inhibit: (1) transcriptional activity of oncogenic c-Myc; (2) PIM1 expression; (3) pro-survival protein Bcl-2 and c-Myc and its target gene MCL1 expression; and (4) the progression of triple-negative breast cancer (figs. 1-3).

price-100[easy_payment currency=”USD”]

Thus, pharmacological formulations encompassing “Cucurbitacin D or its analogues or Cucurbitacin D plus any of the known anticancer drugs in use may be used to treat triple-negative breast tumors (fig.4).

Gualou

Figure1. Cucurbitacin D, found in Trichosanthes kirilowii (Gualou), Phormium tenax, and Luffa amara among others,  as indicated here, inhibits the progression of triple-negative breast tumors via down-regulation of oncoproteins c-Myc, PIM1, Bcl-2, and Mcl-1

phormium-tenax

Figure 2. Phormium tenax

Luffa

Figure 3. Luffa

Image result for Cucurbitacin D

Figure 4. Cucurbitacin D


Details of the research findings

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

Amount: $100

Undisclosed mechanistic information: How Cucurbitacin D increases the expression of cell cycle inhibitor and the tumor suppressor p27, while decreases the expression of oncoproteins c-Myc, Mcl-1, Bcl-2 and PIM1

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References:

Citation: Boominathan, L.,  Natural product-derived therapy for triple-negative breast tumors: Cucurbitacin D, found in Trichosanthes kirilowii (Gualou), Phormium tenax, and Luffa amara among others, increases the levels of cell cycle inhibitor, p27, inhibits pro-survival pathways mediated by c-Myc, and inhibits the progression of triple-negative breast cancer via up-regulation of its target gene, 10/December/2016, 7.21 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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