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.
| Original language | English |
|---|---|
| Journal | Cancer Medicine |
| DOIs | |
| Publication status | Accepted/In press - 2018 Jan 1 |
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Keywords
- Artemisia annua L.
- autophagy
- everolimus
- metastatic renal cell carcinoma
- pyruvate kinase muscle isozyme M2
ASJC Scopus subject areas
- Oncology
- Radiology Nuclear Medicine and imaging
- Cancer Research
Cite this
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. / 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.
In: Cancer Medicine, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Son, Ji Yeon
AU - Yoon, Sungpil
AU - Tae, In Hwan
AU - Park, Yu Jin
AU - De, Umasankar
AU - Jeon, Yukyoung
AU - Park, Young Ju
AU - Rhyu, Im Joo
AU - Lee, Byung Mu
AU - Chung, Kyu Huck
AU - Lim, Joung Eun
AU - Lee, Se Jeong
AU - Lee, Hye Won
AU - Kwak, Jong Hwan
AU - Kim, Hyung Sik
AU - Choi, Han Yong
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - Artemisia annua L.
KW - autophagy
KW - everolimus
KW - metastatic renal cell carcinoma
KW - pyruvate kinase muscle isozyme M2
UR - http://www.scopus.com/inward/record.url?scp=85052839901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052839901&partnerID=8YFLogxK
U2 - 10.1002/cam4.1748
DO - 10.1002/cam4.1748
M3 - Article
C2 - 30160042
AN - SCOPUS:85052839901
JO - Cancer Medicine
JF - Cancer Medicine
SN - 2045-7634
ER -