In:
Cancer Medicine, Wiley, Vol. 7, No. 10 ( 2018-10), p. 5083-5095
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 ( 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.
Type of Medium:
Online Resource
ISSN:
2045-7634
,
2045-7634
DOI:
10.1002/cam4.2018.7.issue-10
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2659751-2
