Novel therapeutic roles of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways

Cancer Medicine
Ji Yeon SonHan Yong Choi

Abstract

Current clinical trials of new anticancer therapies against metastatic renal cell carcinoma (RCC), including molecular-targeted therapies, have not shown promise. The purpose of this study was to preclinically assess the antitumor effects of MC-4, a partially purified material of Artemisia annua L., as a monotherapy or in combination with the known mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, everolimus, against Caki-1 (Von Hippel-Lindau (VHL)+/+) and 786-O (VHL-/-) human RCC cells. MC-4 monotherapy significantly increased tumor growth inhibition and autophagic cell death in RCC cells in vitro and in vivo. Everolimus led to compensatory Akt activation by inhibiting only mTORC1 signaling pathway. In contrast to everolimus, MC-4 enhanced phosphatase and tensin homolog expression and reduced its downstream effector, Akt/pyruvate kinase muscle isozyme M2 (PKM2), leading to decreased expression of glucose transporter 1, which is associated with cancer cell metabolism. The synergistic antitumor and anti-metastatic effects induced by co-administration of MC-4 and everolimus involve cell growth inhibition and autophagic cell death via dual targeting of phosphatidylinositol 3-kinase (PI3K)/Akt/PKM2 and mTORC1. These fin...Continue Reading

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Citations

Nov 14, 2019·International Journal of Molecular Sciences·Prasanta DeyHyung Sik Kim
May 23, 2019·Cancer Cell International·Yanzhu LinXinping Cao
Apr 6, 2019·Frontiers in Cell and Developmental Biology·Prashanta Kumar PandaSovan Sarkar
Apr 7, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bora LimJennifer R Diamond
Nov 3, 2021·Journal of Medicinal Chemistry·Sahil AroraRaj Kumar

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Methods Mentioned

BETA
column chromatography
silica gel column chromatography
column
flow cytometry
protein assay
electrophoresis
xenografts
Transmission
xenograft

Software Mentioned

SigmaPlot
Flowing

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