Combinatorial therapy for metastasis: A pharmacological mixture Simvastatin and Navitoclax/ABT-263 (SAN) inhibits the expression of IL-6/8, decreases the expression of downstream molecules WASF3 and Arp2/3, suppresses tumor cell migration, reduces metastasis and prolongs survival via up regulation of its target gene, 20/February/2019, 12.54 am

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Introduction: What they say:

A study from Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA; Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21218, USA; and Department of Oncology and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA shows that “Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration.” This study was published, in the 26 May issue of the journal “Nature communications” [One of the best journals in General Biology with an I.F of 11.329 plus], by  Prof. and Director of Physical Sciences-Oncology Center (The Johns Hopkins University) Denis Wirtz, Hasini Jayatilaka, 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 metastasis: A pharmacological mixture Simvastatin and Navitoclax/ABT-263 (SAN) inhibits the expression of IL-6/8, decreases the expression of downstream molecules WASF3 and Arp2/3, suppresses tumor cell migration, reduces metastasis and prolongs survival via up regulation of its target gene


From significance of the study to Public health relevance:

Given that: (i) each year nearly 14 million people are diagnosed with cancer globally; (ii) metastasis is common to all forms of cancers; (iii) metastasis is the principle reason for most of the cancer deaths; (iv) even intense multimodal treatment saves only less than 50% of metastatic patients; (iv) our understanding is incomplete in terms of down stream molecular targets and the oncogenic/malignant pathways involved in metastatic cancers; (v) cancer deaths globally are expected to be doubled in the next decade; (vi) 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 patients’ immune system against metastatic tumors (Cancer immunotherapy); (ii) anti-cancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iii) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (iv) a cheaper alternative to the existing expensive anticancer drugs; (v) a side-effect-free natural product-based drug; (vi) increase the therapeutic index of anti-cancer drugs; and (vii) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What we infer from what they say:

Prof. Wirtz’s research team has recently shown that:(1) Interleukin-6 (IL-6) and Interleukin-8 (IL-8) are amplified by cell proliferation and cell density; (2) IL-6 and IL-8 are overexpressed only in metastatic human sarcoma and carcinoma cells, but not in normal cells: (3) increased levels of IL6 and IL-8 may increase the expression of oncogenic WASF3 and Arp2/3 and promote tumor cell migration; promote metastatic capacity of cancer cells; and (4) inhibiting the expression of IL6 and IL8, by treating the metastatic tumors with Tocilizumab and Reparaxin, stalled the metastatic progression, but not the primary tumor growth, suggesting that simultaneous inhibition of IL-6 and IL-8 may inhibit initiation of metastatic process.


From research findings to therapeutic opportunity :

This study suggests a combinatorial therapy for Metastasis.   A pharmacological mixture Simvastatin and Navitoclax/ABT-263 (SAN), by increasing the expression of its target genes, it may decrease the expression of both interleukins, IL-6 and IL-8 (fig. 1). Thereby, it may: (i) inhibit WASF3 and Arp2/3 expression; (ii) stifle tumor cell migration; (iii) decrease metastatic capacity of cancer cells; (iv) dismantle IL6/IL-8-WASF-Arp2/3 signaling network; (v) reduce metastasis; and (vi) promote survival (fig.1).

Thus, pharmacological formulations encompassing “Simvastatin and Navitoclax/ABT-263 (SAN) or their analogues, either alone or in combination with other known anticancer drugs” may be used to inhibit metastatic progression of cancers.
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Figure 1. Mechanistic insights into how  a pharmacological mixture encompassing Simvastatin and Navitoclax/ABT-263 (SAN) suppresses the expression of IL-6/8 and WASF3 and Arp2/3 to stall cancer metastasis.

Figure 2. Combinatorial therapy for cancer metastasis.


Details of the idea posted: 

Idea formulated by: Dr L Boominathan PhD

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Undisclosed mechanistic information: How does a pharmacological mixture Simvastatin and Navitoclax/ABT-263 (SAN) suppress the expression of IL-6/8 and WASF3 and Arp2/3 ?


References:

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

Citation: Boominathan, L., Combinatorial therapy for metastasis: A pharmacological mixture Simvastatin and Navitoclax/ABT-263 (SAN) inhibits the expression of IL-6/8, decreases the expression of downstream molecules WASF3 and Arp2/3, suppresses tumor cell migration, reduces metastasis and prolongs survival via up regulation of its target gene, 20/February/2019, 12.54 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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