Combinatorial therapy for Notch1-overexpressing Human cancers: A therapeutic mix encompassing  Metformin and Navitoclax/ABT-263 (MAN) inhibits the expression of Notch1, and adhesion molecule VCAM1, suppresses neutrophil infiltration and tumor cell adhesion to endothelium and prevents Notch1-driven metastasis via upregulation of its target gene, 15/February/2019, 7.26 am

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Introduction: What they say:

A study from the Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Vascular Biology, CBTM, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120 Heidelberg, Germany; and Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany shows that “Endothelial Notch1 Activity Facilitates Metastasis.” This study was published, in the 12 Feb 2017 issue of the journal “Cancer Cell” [the number 1 journal in Cancer Biology with an I.F of plus 23+], by Prof. Andreas Fischer, Elfriede Wieland, 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 Notch1-overexpressing Human cancers: A therapeutic mix encompassing  Metformin and Navitoclax/ABT-263 (MAN) inhibits the expression of Notch1, and adhesion molecule VCAM1, suppresses neutrophil infiltration and tumor cell adhesion to endothelium and prevents Notch1-driven metastasis via upregulation of its target gene

Price 100

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From Significance of the study to Public health relevance

Given that: (i) each year nearly 14 million people are diagnosed with cancer globally, and little more than half of them will die; (ii) cancer deaths globally are expected to be doubled by 2030; (iii) most of the cancer deaths are due to metastasis; (iv) 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 activate his/her own immune system against tumors (Cancer immunotherapy); (ii) anticancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iii) a cheaper alternative to the existing expensive anticancer drugs; (iv) a side-effect-free natural product-based drug; (v) increase the therapeutic index of anti-cancer drugs; and (vi) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What we infer from what they say:

Prof. Andreas Fischer’s research team has recently shown that activated Notch1 receptors (N1ICD): (1) are frequently overexpressed in endothelial cells of human carcinomas and melanoma; (2) promote neutrophil infiltration; (3) promote tumor cell adhesion to the endothelium; (4) induce intravasation; (5) promote lung colonization; (6) promote post-surgical metastasis; (7) inhibit the expression of cell adhesion molecule VCAM1; and (8) inhibit invasion, migration, and metastasis. Further, they have shown that inhibition of Notch1 or VCAM1 expression stalls peritoneal neutrophil infiltration and metastatic progression of cancers.


From research findings to therapeutic opportunity :

This study suggests a combinatorial therapy for metastatic tumors. A pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263 (MAN), by increasing the expression of its target genes, it may decrease the expression of Notch1 and its downstream signaling (fig. 1). Thereby, it may: (i) inhibit the expression of adhesion molecule VCAM1; (ii) suppress neutrophil infiltration; (iii) suppress tumor cell adhesion to the endothelium; and (iv) inhibit invasion, migration, and metastasis.

Figure 1. Mechanistic insights into how a pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263 (MAN) suppresses the expression of Notch-1 and VCAM and inhibits metastatic progression. And thereby, functions as an antimetastatic agent.

Figure 2. Combinatorial therapy for metastatic cancers. 

Thus, pharmacological formulations encompassing “Metformin and Navitoclax/ABT-263 (MAN), either alone or in combination with other known anticancer drugs,” (fig.1) may be used to inhibit the metastatic progression of cancers, including metastatic melanoma.


Details of the Research findings:

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

Amount: $500#

Undisclosed mechanistic information: How does a therapeutic mix encompassing Metformin and Navitoclax/ABT-263 (MAN) decrease the expression of Notch-1 and VCAM?

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References:

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Citation: Boominathan, L., Combinatorial therapy for Notch1-overexpressing Human cancers: A therapeutic mix encompassing  Metformin and Navitoclax/ABT-263 (MAN) inhibits the expression of Notch1, and adhesion molecule VCAM1, suppresses neutrophil infiltration and tumor cell adhesion to endothelium and prevents Notch1-driven metastasis via upregulation of its target gene, 15/February/2019, 7.26 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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