[janimcdo]

GLUT4-selective antagonists for multiple myeloma?

by janimcdo on Mon Sep 30, 2019 5:36 pm

Hi All

I am currently in remission and want to stay that way. (Don't we all?)

My research has focused on things I can do like diet. During my research, I came across this paper about a possible metabolic solution to myeloma. Does anyone know more about this possibility?

Janice

Reference:

Wei, C, et al, "Development of GLUT4-selective antagonists for multiple myeloma therapy," European Journal of Medicinal Chemistry, October 20, 2017 (abstract)

Abstract:

Cancer cells consume more glucose to fuel metabolic programs fundamental to sustaining their survival, growth and proliferation. Among the fourteen SLC2A family members, GLUTs 1 and 4 are high-affinity glucose transporters. GLUT4 (SLC2A4) is highly expressed in muscle and adipose tissue. Basally retained within the cell, GLUT4 traffics to the plasma membrane (PM) in response to insulin and exercise-stimulation. The plasma cell malignancy multiple myeloma (multiple myeloma) exhibits increased constitutive expression of GLUT4 on the PM, co-opting use of GLUT4 for survival and proliferation. GLUT4 inhibition by knockdown or treatment with the FDA-approved HIV protease inhibitor ritonavir leads to cytostatic and/or cytotoxic and chemosensitizing effects in tumor cells both in vitro and in vivo. We recently reported our generation of GLUT4 homology models and virtual high-throughput screening (vHTS) to identify multiple series of novel GLUT4 antagonists. In this report, we describe our initial hit-to-lead optimization to synthesize new analogs with improved potency and selectivity for GLUT4, and the biological characterization of these compounds in a variety of assays. We show that our lead compound (compound 20) decreases glucose uptake and cell proliferation as well as inhibits the expression of pro-survival MCL-1 in multiple myeloma similar to the effect observed via knockdown of GLUT4 expression. Compound 20 is also effective at chemosensitizing multiple myeloma cell lines and patient samples to venetoclax, dexamethasone and melphalan. In sum, we report development of selective GLUT4 inhibitors lacking inhibitory activity against GLUT1 and GLUT8. We show that selective pharmacological inhibition of GLUT4 is feasible and this may represent a novel strategy for the treatment and chemosensitization of multiple myeloma to standard therapeutics.

[WholeNotherWorld]

Re: GLUT4-selective antagonists for multiple myeloma?

by WholeNotherWorld on Thu Oct 03, 2019 9:24 am

Great article. Very interesting.

[Foundry738]

Re: GLUT4-selective antagonists for multiple myeloma?

by Foundry738 on Sat Oct 05, 2019 3:13 pm

Hi Janice,

This is a very interesting article, but it doesn't do much directly regarding diet since it focuses on making treatments more effective by selectively sensitizing the cancer cells. It doesn't imply that dramatically reducing glucose, or simple carbohydrates by extension, will affect the cancer cells.