Introduction: What they say:
A study from the Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA shows that “Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1.” This study was published, in the 30 August 2017 issue of the journal “Cell Stem cell” [One of the best journals in Stem cell Biology with an I.F of 22.387], by Prof. Xue HH and Li F and others.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Probiotic-based chemotherapy targeting immune-inhibitory receptors and cancer stem cells in chronic myelogenous leukemia (CML) and other metastatic cancers: A pharmaceutical mixture encompassing Misoprostol, an FDA-approved EP4 agonist and abortion-promoting drug, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as IL-1β, VHL, p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets CML leukemic stem cells, confers protection against CML and prolongs survival, via up-regulation of its target gene
From Significance of the study to Public health relevance:
First, given that: (i) each year nearly 14 million people are diagnosed with cancer globally; (ii) cancer deaths globally are expected to be doubled in the next decade; (iii) metastasis is the principal reason for most of the cancer deaths; (iv) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (v) a way to activate patients’ immune system against tumors (Cancer immunotherapy); (vi) anti-cancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (vii) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (viii) a cheaper alternative to the existing expensive anticancer drugs; (ix) a side-effect-free natural product-based drug; (x) increase the therapeutic index of anti-cancer drugs; and (xi) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant 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, there is an urgent need to find a way to effectively treat and stall metastatic progression and relapse of mutant p53-overexpressing human cancers.
What we infer from what they say:
Given that chronic myelogenous leukemia (CML) cannot be eradicated without the elimination of CML leukemic stem cells, there is an urgent unmet clinical need to find drugs that specifically target CML leukemic stem cells. A number of studies suggest that CML leukemic stem cells require Tcf1 and Lef1 factors for self-renewal.
Prof.Xue’s research team has recently shown/suggested that:(1) prostaglandin E1 (PGE1) treatment inhibits the activity of CML leukemia stem cells; (2) PGE1 inhibits the expression of Fosb and Fos AP-1 factors through the EP4 receptor; (3) the EP4 agonist Misoprostol protects against CML; and (4) subjecting CML patients to undergo combinatorial therapy, with PGE1/misoprostol and conventional tyrosine-kinase inhibitors, may cure CML, suggesting that activating the PGE1-EP4 pathway may specifically target CML leukemic stem cells and eradicate/cure CML.
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: The EP4 agonist Misoprostol had been shown target CML leukemic stem cells and confer protection against CML. However, the detailed mechanistic insights are yet to emerge. Misoprostol, by increasing the expression of its target genes, it may decrease the expression of Fosb and Fos AP-1 factors and other oncogenes (fig. 1). Thereby, it may: (i) increase the expression of tumor suppressor genes, such as IL-1β, VHL; (ii) increase the expression of a number of other tumor suppressor genes, including p53, and TA-p73/p63 (Figure 1);(iii) activate the PGE1-EP4 network; (iii) inhibit the activity and proliferation of CML leukemia stem cells; (iv) inhibit CML growth; and (v) promote survival. Thus, a pharmacological formulation encompassing “Misoprostol or its analogs, either alone or in combination with other known anticancer drugs, or probiotics enriched with anti-cancer activity, such as Lactobacillus rhamnosus (1.0×103 CFU/ml),” may be used to inhibit the progression of advanced cancers and promote disease-free survival (Figure 3).
(iii) Therapeutic opportunity: Given the ability of Misoprostol to induce the expression of a number of tumor/metastasis suppressor genes, it may be used, either alone or in combination with other anticancer drugs, to inhibit the progression of CML and other p53-mutated invasive metastatic tumors. Taken together, this study suggests, for the first time, that oncologists may consider treating cancer patients with Misoprostol, as it may stall the progression of CML; and other advanced metastatic cancers. (figure 2).
Details of the Research findings:
Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.
Undisclosed mechanistic information: How does Misoprostol increase the expression of tumor/metastatic suppressors IL-1β, VHL, and others?
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Citation: Boominathan, L., Probiotic-based chemotherapy targeting immune-inhibitory receptors and cancer stem cells in chronic myelogenous leukemia (CML) and other metastatic cancers: A pharmaceutical mixture encompassing Misoprostol, an FDA-approved EP4 agonist and abortion-promoting drug, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as IL-1β, VHL, p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets CML leukemic stem cells, confers protection against CML and prolongs survival, via up-regulation of its target gene, 10/April/2018, 12.09 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org
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