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. (29th August 2018)

• Record Type: Journal Article
• Authors: 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, Kyu‐Huck; Lim, Joung Eun; Lee, Se Jeong; Lee, Hye Won; Kwak, Jong Hwan; Kim, Hyung Sik; Choi, Han Yong
• Is Part Of: Cancer medicine. Volume 7:Number 10(2018:Oct.)
• Page Start: 5083
• Page End: 5095
• Publication Date: 2018-08-29
• Subjects: Artemisia annua L. -- autophagy -- everolimus -- metastatic renal cell carcinoma -- pyruvate kinase muscle isozyme M2; 616.994005
• DOI: 10.1002/cam4.1748
• Languages: English
• ISSNs: 2045-7634

Abstract

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 findings suggest that MC‐4 is a novel Akt/PKM2 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. Abstract : In this report, we investigated the anti‐tumor efficacy of MC‐4, a subfraction from Artemisia annua L. alone and combined with everolimus in against Caki‐1 (Von Hippel‐Lindau (VHL) wild type) and 786‐O (VHL null) human renal cancer cells. We found that synergistic inhibition of tumor growth and metastasis through enhanced cell cycle arrest and autophagic cell death by MC‐4 and everolimus was mediated by dual inhibition of PKM2 and mTOR pathways. This study provides additional insight into the mechanism(s) of action of everolimus that can be used to enhance the utility of mTOR inhibitors as part of combination therapy for metastatic renal cell carcinoma.