Targeting 3-phosphoinositide-dependent protein kinase 1 associated with drug-resistant renal cell carcinoma using new oridonin analogs.
The current agents used for renal cell carcinoma (RCC) only exhibit the moderate response rate among patients. Development of drug resistance eventually fuels the need of either more potent drugs or new drugs to target the resistant pathways. Oridonin is a diterpenoid isolated from the Chinese medicinal herb Rabdosia rubescens and has been shown to have antitumor activities in many cancers. We previously developed new synthetic methodologies to modify structurally diversified diterpenoids and designed a series of nitrogen-enriched oridonin analogs. In this study, we screened a variety of oridonin analogs based on their cytotoxicity using MTT assay and identify the most potent candidate, namely, CYD-6-17. CYD-6-17 exhibited a high potency to inhibit the in vitro growth of several drug-resistant RCC cells as well as endothelial cells stimulated by tumor cells at nanomolar range. Delivery of CYD-6-17 significantly inhibited RCC tumor growth using xenograft model. Mechanistically, it targeted the 3-phosphoinositide-dependent protein kinase 1 gene that appeared to be a potent regulator of AKT and was associated with patient survival after targeted therapies. This offers a new rational therapeutic regimen of CYD-6-17 to drug-resistant RCC based on its novel mechanism of action.
Department of Urology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, P.R. China.|Institute of Urology, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.
Jiancheng
J
Zhou
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Eun-Jin
EJ
Yun
Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.|Institute of Urology, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.
Wei
W
Chen
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Ye
Y
Ding
Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.|Institute of Urology, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.
Kaijie
K
Wu
Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.|Institute of Urology, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.
Bin
B
Wang
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Chunyong
C
Ding
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Elizabeth
E
Hernandez
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
John
J
Santoyo
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Rey-Chen
RC
Pong
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Haiying
H
Chen
Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.|Institute of Urology, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.
Dalin
D
He
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Jia
J
Zhou
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jer-Tsong
JT
Hsieh
D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D045786:Diterpenes, Kaurane; C011959:oridonin; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D051057:Proto-Oncogene Proteins c-akt