Hydrocinchonine, cinchonine, and quinidine potentiate paclitaxel-induced cytotoxicity and apoptosis via multidrug resistance reversal in MES-SA/DX5 uterine sarcoma cells.
Multidrug resistance (MDR) is one of important issues to cause the chemotherapy failure against cancers including gynecological malignancies. Despite some MDR reversal evidences of natural compounds including quinidine and cinchonine, there are no reports on MDR reversal activity of hydrocinchonine with its analogues quinidine and cinchonine especially in uterine sarcoma cells. Thus, in the current study, we comparatively investigated the potent efficacy of hydrocinchonine and its analogues quinidine and cinchonine as MDR-reversal agents for combined therapy with antitumor agent paclitaxel (TAX). Hydrocinchonine, cinchonine, and quinidine significantly increased the cytotoxicity of TAX in P-glycoprotein (gp)-positive MES-SA/DX5, but not in the P-gp-negative MES-SA cells at nontoxic concentrations by 3-(4,5-dimethylthiazol-2-yl)-2,5--diphenyltetrazolium bromide (MTT) assay. Rhodamine assay also revealed that hydrocinchonine, cinchonine, and quinidine effectively enhanced the accumulation of a P-gp substrate, rhodamine in TAX-treated MES-SA/DX5 cells compared with TAX-treated control. In addition, hydrocinchonine, cinchonine, and quinidine effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-3, and downregulated P-gp expression as well as increased sub-G1 apoptotic portion in TAX-treated MES-SA/DX5 cells. Taken together, hydrocinchonine exerted MDR reversal activity and synergistic apoptotic effect with TAX in MES-SA/DX5 cells almost comparable with quinidine and cinchonine as a potent MDR-reversal and combined therapy agent with TAX.
Lee
Sang-Yun
SY
College of Oriental Medicine, Kyung Hee University, 1 Hoegidong, Dongdaemungu, Seoul 130-701, Republic of Korea.
Rhee
Yun-Hee
YH
Jeong
Soo-Jin
SJ
Lee
Hyo-Jeong
HJ
Lee
Hyo-Jung
HJ
Jung
Min-Hyung
MH
Kim
Sun-Hyung
SH
Lee
Eun-Ok
EO
Ahn
Kwang Seok
KS
Ahn
Kyoo Seok
KS
Kim
Sung-Hoon
SH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002930:Cinchona Alkaloids / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D017239:Paclitaxel / Q000633:toxicity*; D011802:Quinidine / Q000633:toxicity; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology*; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002930:Cinchona Alkaloids; D011802:Quinidine; D017239:Paclitaxel; C010086:cinchonine