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Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in advanced metastatic cancers: A pharmaceutical mixture encompassing Pimozide, an antipsychotic drug, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as KIBRA, p57Kip2,   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, 8/December/2018, 7.26 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 Pimozide, an antipsychotic drug, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as KIBRA, p57Kip2,   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: Pimozide had been shown to inhibit cancer progression. However, the mechanism of action remains largely unknown. This study suggests, for the first time, that Pimozide, 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 KIBRA, and p57Kip2; (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 Pimozide and probiotic Lactobacillus rhamnosus  (1.0×103 CFU/ml). Thus, a pharmacological formulation encompassing “Pimozide 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  Pimozide increases the expression of tumor/metastatic suppressors, such as TPM1, CCM3/KRIT1,  p53, TAp73/p63, INK4a, p19ARF and others.

Figure 2. Pimozide  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 “Pimozide 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 Pimozide 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 Pimozide, an antipsychotic drug, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as KIBRA, p57Kip2,   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, 8/December/2018, 7.26 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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