title: Co-treatment with the anti-malarial drugs mefloquine and primaquine highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition.
abstract: The purpose of this study was to identify conditions that will increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Currently, atovaquine (ATO), chloroquine (CHL), primaquine (PRI), mefloquine (MEF), artesunate (ART), and doxycycline (DOY) are the most commonly used anti-malarial drugs. Herein, we tested whether anti-malarial drugs can sensitize drug-resistant KBV20C cancer cells. None of the six tested anti-malarial drugs was found to better sensitize the drug-resistant cells compared to the sensitive KB cells. With an exception of DOY, all other anti-malarial drugs tested could sensitize both KB and KBV20C cells to a similar extent, suggesting that anti-malarial drugs could be used for sensitive as well as resistant cancer cells. Furthermore, we examined the effects of anti-malarial drugs in combination with an antimitotic drug, vinblastine (VIN) on the sensitisation of resistant KBV20C cells. Using viability assay, microscopic observation, assessment of cleaved PARP, and Hoechst staining, we identified that two anti-malarial drugs, PRI and MEF, highly sensitized KBV20C-resistant cells to VIN treatment. Moreover, PRI- or MEF-induced sensitisation was not observed in VIN-treated sensitive KB parent cells, suggesting that the observed effect is specific to resistant cancer cells. We demonstrated that the PRI and MEF sensitisation mechanism mainly depends on the inhibition of p-glycoprotein (P-gp). Our findings may contribute to the development of anti-malarial drug-based combination therapies for patients resistant to anti-mitotic drugs.
authors.affiliation: Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Ju-Hwa
authors.initials: JH
authors.lastname: Kim
authors.forename: Ae-Ran
authors.initials: AR
authors.lastname: Choi
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Kim
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D015767:Mefloquine / Q000494:pharmacology*; D011319:Primaquine / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D014747:Vinblastine; D000077332:Artesunate; D002738:Chloroquine; D014700:Verapamil; D011319:Primaquine; D004318:Doxycycline; D015767:Mefloquine
keywords: ART; ATO; Anti-malarial drugs; C-PARP; CHL; DMSO; DOY; Drug-resistance; FACS; FBS; MEF; Mefloquine; P-gp; PBS; PRL; Primaquine; RT; SDS–PAGE; TCA; VER; VIN; Vinblastine; artesunate; atovaquone; chloroquine; cleaved ploy ADP ribose polymerase; dimethylsulfoxide; doxycycline; fetal bovine serum; fluorescence-activated cell sorting; mefloquine; p-glycoprotein; phosphate buffered saline; primaquine; room temperature; sodium dodecyl sulfate–polyacrylamide gel electrophoresis; trichloroacetic acid; verapamil; vinblasitne