Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors


The cover for issue 24 of Oncotarget features Figure 6, "In vivo xenograft studies in WiDr and MDA-MB-231 tumor models," by Jonnalagadda, et al.

In vitro effects on extracellular flux via glycolysis and mitochondrial stress tests suggest that candidate compounds 3 and 9 disrupt glycolysis and Ox Phos efficiently in MCT1 expressing colorectal adenocarcinoma Wi Dr and MCT4 expressing triple negative breast cancer MDA-MB-231 cells.

Fluorescence microscopy analyses in these cells also indicate that compound 9 is internalized and concentrated near mitochondria.

Dr. Lester R. Drewes from the Integrated Biosciences Graduate Program and the Department of Biomedical Sciences, Medical School Duluth at the University of Minnesota, in Duluth, MN 55812, USA and Dr. Venkatram R. Mereddy from the Integrated Biosciences Graduate Program, the Department of Pharmacy Practice & Pharmaceutical Sciences and the Department of Chemistry and Biochemistry at the University of Minnesota in Duluth, MN 55812, USA said "Metabolic reprogramming is now recognized as a critical hallmark of cancer and by understanding and manipulating the energetics of tumor metabolism, new therapeutic strategies may be developed for the treatment of cancer"

Figure 6: In vivo xenograft studies in WiDr and MDA-MB-231 tumor models.

Glycolysis is generally amplified in cancer cells to keep up with bioenergetic and biosynthetic demands for rapid cell proliferation.

In this regard, inhibition of Ox Phos will lead to severe ATP depletion and dysfunction of the TCA cycle, again starving cancer cells of critical components for cell survival and proliferation.

Monocarboxylic acid transport is one of the metabolic targets wherein the flux of small ketone bodies such as lactic acid and pyruvic acid occurs to support metabolic demands in cancer cells.

MCT1 and MCT4 are encoded by the genes SCL16A1 and SLC16A3 and they also play an active role in the shuttling of lactate from glycolytic cancer cells into the neighboring oxidative cells for energy generation via mitochondrial Ox Phos. The Drewes/Mereddy research team concluded, "We carried out in vitro cell proliferation inhibition studies of these inhibitors in MCT1 and MCT4 expressing cancer cells and identified compound 9 as a lead candidate for further studies.

Compound 3 was evaluated for its in vivo efficacy in Wi Dr tumor model in mice and compared it with 9 and this study indicated that both these inhibitors exhibited similar anticancer efficacy.

Compound 9 was further advanced for in vivo study in MDA-MB-231 tumor xenograft models in mice and these results indicated that 9 significantly inhibited tumor growth as a single agent."

Full text - https://doi.org/10.18632/oncotarget.26760

Correspondence to - Lester R. Drewes - [email protected] and Venkatram R. Mereddy - [email protected]

Keywords - monocarboxylate transporter 1 inhibitor, monocarboxylate transporter 4 inhibitor, 2-alkoxy-N,N-dialkyl cyanocinnamic acid, cancer, metabolism

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