Open AccessNovel 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
Author(s) -
Son Ji Yeon,
Yoon Sungpil,
Tae In Hwan,
Park Yu Jin,
De Umasankar,
Jeon Yukyoung,
Park Young Ju,
Rhyu Im Joo,
Lee Byung Mu,
Chung KyuHuck,
Lim Joung Eun,
Lee Se Jeong,
Lee Hye Won,
Kwak Jong Hwan,
Kim Hyung Sik,
Choi Han Yong
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1748
Subject(s) - everolimus , renal cell carcinoma , protein kinase b , pi3k/akt/mtor pathway , cancer research , isozyme , pharmacology , chemistry , medicine , endocrinology , phosphorylation , biochemistry , enzyme , signal transduction
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 ( mTORC 1) 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 mTORC 1 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 ( PKM 2), 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 ( PI 3K)/Akt/ PKM 2 and mTORC 1. These findings suggest that MC ‐4 is a novel Akt/ PKM 2 inhibitor that can overcome the limitation of existing mTOR inhibitors and can be considered a novel strategy to treat patients with rapidly progressing advanced RCC.