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Combinatorial therapy for Cancer: A therapeutic mix encompassing Gedunin,  Atorvastatin, Desipramine, Sulfasalazine (SSZ), SAHA(suberanilohydroxamic acid)/Vorinostat (GADSS)  increases the expression of REV-ERBa, inhibits glioblastoma proliferation, increases interferon-IFNγ signalling, increase antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival, via up-regulation of its target gene, 21/February/2018, 6.55 am

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Introduction:What they say:

A recent study from Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA and Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037, USA shows that “Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence”. This study was published, in the 10 January 2018 issue of Nature medicine (one of the best journals in bio-medicine with an impact factor of 29 plus), by Profs. Panda, Verma IM, and Sulli 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 Cancer: A therapeutic mix encompassing Gedunin Atorvastatin, DesipramineSulfasalazine (SSZ), SAHA(suberanilohydroxamic acid)/Vorinostat (GADSS)  increases the expression of REV-ERBa, inhibits glioblastoma proliferation, increases interferon-IFNγ signalling, increase antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival, via up-regulation of its target gene


From significance of the study to Public health relevance: 

Given that: (i) glioblastoma is the most aggressive cancer and it accounts for 15% of all brain cancers; (ii) the chances of survival of people diagnosed with glioblastoma are less than one-and-a-half-years; (iii) Epidermal growth factor receptor (EGFR) gene is either overexpressed or carries an extra copy in classical subtype of glioblastoma; (iv) Glioblastoma multiforme (GBM) is resistant to apoptosis induced by conventional chemotherapeutic agents; (v) the molecular pathways involved in the development of glioblastoma are not completely understood yet; (iv) blockade of immune evasion molecules, such as PD-1, is effective only in minority of cancer patients; (iv) each year nearly 14 million people are diagnosed with cancer globally; (v) cancer deaths globally are expected to be doubled in the next decade; (vi) metastasis is the principle reason for most of the cancer deaths; (vii) cancer treatment 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 effectively activate patients’ immune system against tumors (Cancer immunotherapy); (ii) a way to improve the efficacy of immunotherapy by targeting more immune evasion molecules at a time; (iii) anti-cancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iv) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (v) a cheaper alternative to the existing expensive anticancer drugs; (vi) a side-effect-free natural product-based drug; (vii) increase the therapeutic index of anti-cancer drugs; and (viii) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What is known?

Peturbans in circadian rhythm, that has been shown to maintain daily rhythm, results in alteration in (1) Proliferation; (2) Metabolism; (3) Inflammation; and (4) DNA damage response. The nuclear hormone receptors REV-ERBa/NR1D1 and REV-ERBb/NR1D2 have been shown to function as essential components of circadian clock.

Profs Panda’s and Verma’s research team have shown recently that agonists that activate REV-ERBs: (i) are toxic to cancer cells and oncogene-induced senescent cells, without being excessively toxic to normal cells; (ii) inhibit oncogenic driver proteins such as HRAS, BRAF and PIK3CA; (iii) evoke apoptotic response through inhibition of lipogenesis and autophagy; (iv) stall glioblastoma growth in vivo; (v) ameriorate survival, without being excessively toxic to normal cells; (vi) inhibit the expression of oncosurvival proteins; and stabilize/activate tumor suppressor genes; and (vii) inhibit cancer progression, including glioblastoma progression, suggesting that combinatorial inhibition of oncogenic signalling, and activation of REV-ERBs and other tumor suppressor genes may stall cancer progression, including glioblastoma progression.


From Research Findings to Therapeutic opportunity:

A therapeutic mix encompassing Gedunin Atorvastatin, DesipramineSulfasalazine (SSZ), SAHA(suberanilohydroxamic acid)/Vorinostat (GADSS), by increasing the expression of its target gene, it may decrease and increase oncoproteins and REV-ERBs/tumor suppressor expression, respectively (fig. 1). Thereby, it may: (i) diminish the expression of a number of immune evasion molecules in cancer cells; (ii) increase IFNγ signaling; (iii) increase antigen presentation; (iv) augment unfolded protein response: (v) increase the number of tumor-infiltrating immune cells; (vi) increase T-cell anti-tumor immunity; (vii) inhibit tumor proliferation; (viii) decrease tumor burden and promote growth suppression; (ix) increase survival of patients with cancer; and (x) increase the efficacy of cancer immunotherapy (fig. 1).

Figure 1. Mechanistic insight into how Gedunin Atorvastatin, DesipramineSulfasalazine (SSZ), SAHA(suberanilohydroxamic acid)/Vorinostat (GADSS)  increases REV-ERBs and other tumor suppressor proteins.

Figure 2. The chemical structure of Gedunin Atorvastatin, DesipramineSulfasalazine (SSZ), SAHA(suberanilohydroxamic acid)/Vorinostat (GADSS) that function as  an anticancer agent. 

Figure 3 GADSS may function as an anti-cancer agent through induction of REV-ERB and other tumor suppressor genes

 

Thus, pharmacological formulations encompassing “Gedunin Atorvastatin, DesipramineSulfasalazine (SSZ), SAHA(suberanilohydroxamic acid)/Vorinostat (GADSS)  or their analogues, either alone or in combination with other drugs“ may be used to (i) inhibit the progression of cancers, including glioblastoma; and (ii) enhance the efficacy of Cancer immunotherapy (fig. 2).


Details of the research findings:

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

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

Amount: $750#

Undisclosed mechanistic information: How a therapeutic mix encompassing Gedunin Atorvastatin, DesipramineSulfasalazine (SSZ), SAHA(suberanilohydroxamic acid)/Vorinostat (GADSS) increases the expression of REV-ERBa and a number of other tumor suppressor genes

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References:

Citation: Boominathan, L., Combinatorial therapy for Cancer: A therapeutic mix encompassing Gedunin Atorvastatin, DesipramineSulfasalazine (SSZ), SAHA(suberanilohydroxamic acid)/Vorinostat (GADSS)  increases the expression of REV-ERBa, inhibits glioblastoma proliferation, increases interferon-IFNγ signalling, increase antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival, via up-regulation of its target gene, 21/February/2018, 6.54 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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