Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in advanced metastatic cancers: A pharmaceutical mixture encompassing   SAHA (Suberoylanilide Hydroxamic Acid) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CCM3/KRIT1, p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets ovarian cancer stem cells, confers protection against chemoresistance and prolongs survival, via up-regulation of its target gene, 13/December/2018, `11.01 pm

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What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, the Director-cum-chief Scientist of GBMD, reports that: Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in advanced metastatic cancers: A pharmaceutical mixture encompassing   SAHA (Suberoylanilide Hydroxamic Acid) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CCM3/KRIT1, p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets ovarian cancer stem cells, confers protection against chemoresistance and prolongs survival, via up-regulation of its target gene


The Significance of the study to Public health relevance:

First, 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 at present; (ii) cancer deaths globally are expected to be doubled by 2030;  and (iii) 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 anticancer drugs that target cancer stem cells; and (iv) a way to effectively treat and prevent metastatic progression and relapse of ovarian cancers.

Second, given that: (1) cancer suppressor p53 is mutated in more than 50% of human cancers of different tissue origin; (2) p53 pathway is altered in about 80% of tumors; (3) our understanding is incomplete in terms of molecular targets and the oncogenic/malignant pathways involved in mutant p53-overexpressing tumors; (4) cancer causes the highest economic loss compared to all the known causes of death worldwide; and (5) cancer causes the considerable economic loss worldwide, there is an urgent need to find a way to effectively treat and stall metastatic progression and relapse of mutant p53-overexpressing human cancers.


From research findings to therapeutic opportunity :

(i) Therapeutic strategy:

This study suggests a therapeutic strategy for stalling the progression of p53-deficient/deleted or mutant-p53 expressing metastatic cancers. By activating tumor suppressor p53’s unmutated “homologous protein such as TAp73/p63” in p53-deficient or mutant-p53 expressing metastatic cancer cells, one can stall their progression.

(ii) Research findings: Suberoylanilide Hydroxamic Acid (SAHA), a Histone deacetylase (HDAC) inhibitor, has been shown to inhibit cancer progression. However, the mechanism of action remains largely unknown. This study suggests, for the first time, that MiRNA-129, by increasing the expression of its target genes, it may: (i) decrease the expression of a number of oncogenes and DNA repair proteins; (ii) increase the expression of tumor/metastasis suppressor genes, such as TPM1, and CCM3/KRIT1; (iii) increase the expression of a number of other tumor suppressor genes, including p53/TA-p73/p63, and their target genes, INKa/p19ARF and others (Figure 1);(iv) activate tumor/metastasis suppressor network; (v) inhibit immunosuppressive/immune-inhibitory receptors/ molecules; (vi) inhibit the activity and proliferation of cancer stem cells; (vii) inhibit tumor growth; and (viii) promote survival (Figures 1-2). Further, the efficacy of Olaparib can be increased by treating cancer patients with a pharmaceutical mixture encompassing SAHA and probiotic Lactobacillus rhamnosus  (1.0×103 CFU/ml). Thus, a pharmacological formulation encompassing “ SAHA or its analogs, either alone or in combination with other known anticancer drugs, or probiotics enriched with anti-cancer activity, such as  Lactobacillus rhamnosus,” may be used to inhibit the progression of advanced  cancers and promote disease-free survival (Figure 3)

Figure 1. Mechanistic insights into how  SAHA increases the expression of tumor/metastatic suppressors, such as TPM1, CCM3/KRIT1,  p53, TAp73/p63, INK4a, p19ARF and others.

Figure 2.SAHA functions as a tumor/metastatic suppressors agent not only in advanced cancers but also in mutant-p53 expressing human tumors

Figure 3. A pharmacological formulation encompassing “SAHA and probiotic Lactobacillus rhamnosus” may attenuate the progression of advanced  cancers through induction of tumor/metastatic suppressors, such as TPM1, CCM3/KRIT1,  p53, TAp73/p63, INK4a, p19ARF and others

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 SAHA increase the expression of tumor/metastatic suppressors TPM1, CCM3/KRIT1, and others?

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References:

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

Citation: Boominathan, L., Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in advanced metastatic cancers: A pharmaceutical mixture encompassing   SAHA (Suberoylanilide Hydroxamic Acid) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CCM3/KRIT1, p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets ovarian cancer stem cells, confers protection against chemoresistance and prolongs survival, via up-regulation of its target gene, 13/December/2018, `11.01 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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