title: Anti-malarial Drugs Primaquine and Chloroquine Have Different Sensitization Effects with Anti-mitotic Drugs in Resistant Cancer Cells.
abstract: The purpose of this study was to identify conditions that would increase the sensitivity of drug-resistant cancer cells. Previously, two anti-malarial drugs, chloroquine (CHL) and primaquine (PRI), showed different sensitization effects for vinblastine (VIB)-resistant cancer cells. Herein, we tested co-treatment of cells with CHL or PRI and other microtubule-targeting cancer drugs, namely, vinorelbine (VIO), paclitaxel (PAC), docetaxel (DOC), vincristine (VIC), or halaven (HAL). We found that PRI sensitized P-glycoprotein (P-gp)-overexpressing drug-resistant KBV20C cells to all six anti-mitotic drugs to a similar extent. CHL had a similar sensitization effect only for co-treatment with PAC, DOC, VIC, and HAL, while the sensitization effect was less marked for co-treatment with VIB or VIO. FACS analysis and western blot analysis revealed that G2arrest and apoptosis showed only a slight increase on co-treatment with VIB or VIO and CHL. We also found that phospho-histone H3 and pRb were markedly increased only by PRI-VIB co-treatment, but not by CHL-VIB co-treatment. This suggests that reduction in the expression of these proteins correlates with decreased G2arrest in CHL-VIB co-treatment. We further compared the effect of another anti-malarial drug, mefloquine (MEF), in combination with the six anti-mitotic drugs. We found that MEF and PRI had similar sensitization effects in co-treatment with these anti-mitotic drugs. PRI and MEF had generally similar sensitization effects in co-treatment with anti-mitotic drugs, suggesting that they do not have any preferred anti-mitotic drug partner in co-treatment. This indicates that only CHL shows specificity in co-treatment with anti-mitotic drugs in resistant cancer cells. Our results may contribute to the choice of anti-mitotic drugs to be used in co-treatment of resistant cancer cells with the anti-malarial drugs, CHL, PRI, and MEF.
authors.affiliation: Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Ae-Ran
authors.initials: AR
authors.lastname: Choi
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.affiliation: Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Yeon Hwa
authors.initials: YH
authors.lastname: Woo
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do, Republic of Korea syoon88@gmail.com yoons@ncc.re.kr.
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D011319:Primaquine / Q000494:pharmacology*; D043823:Taxoids; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D014747:Vinblastine; D002738:Chloroquine; D011319:Primaquine; D017239:Paclitaxel; D000077235:Vinorelbine
keywords: Anti-malarial drugs; P-gp; drug resistance; mefloquine; primaquine; vinblastine