title: P-glycoprotein mediates the collateral sensitivity of multidrug resistant cells to steroid hormones.
abstract: The overexpression of P-glycoprotein (P-gp, ABCB1) in cancer cells often leads to multidrug resistance (MDR) through reduced drug accumulation. However, certain P-gp-positive cells display hypersensitivity, or collateral sensitivity, to certain compounds that are believed to induce Pgp-dependent oxidative stress. We have previously reported that MDR P-gp-positive CHO cells are collaterally sensitive to verapamil (VRP; Laberge et al. (2009) [1]). In this report we extend our previous findings and show that drug resistant CHO cells are also collaterally sensitive to physiologic levels of progesterone (PRO) and deoxycorticosterone (DOC). Both PRO and DOC collateral sensitivities in CH(R)C5 cells are dependent on P-gp-expression and ATPase, as knockdown of P-gp expression with siRNA or inhibition of P-gp-ATPase with PSC833 reverses PRO- and DOC-induced collateral sensitivity. Moreover, the mitochondrial complexes I and III inhibitors (antimycin-A and rotenone, respectively) synergize with PRO and DOC-induced collateral sensitivity. We also show that VRP inhibits PRO and DOC collateral sensitivity, consistent with earlier findings relating to the VRP's modulation of PRO and DOC-stimulation of P-gp ATPase. The findings of this study demonstrate a P-gp-dependent collateral sensitivity of MDR cells in the presence of physiologically achievable concentrations of progesterone and deoxycorticosterone.
authors.affiliation: Institute of Parasitology, McGill University, Ste. Anne de Bellevue (Montréal), Québec, Canada.
authors.forename: Rémi-Martin
authors.initials: RM
authors.lastname: Laberge
authors.affiliation: Institute of Parasitology, McGill University, Ste. Anne de Bellevue (Montréal), Québec, Canada.
authors.forename: Raghuram
authors.initials: R
authors.lastname: Ambadipudi
authors.affiliation: Institute of Parasitology, McGill University, Ste. Anne de Bellevue (Montréal), Québec, Canada. Electronic address: Elias.Georges@McGill.CA.
authors.forename: Elias
authors.initials: E
authors.lastname: Georges
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000008:administration & dosage / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003524:Cyclosporins / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000008:administration & dosage / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology*; D004357:Drug Synergism; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors; D055785:Gene Knockdown Techniques; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000008:administration & dosage / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D045222:Electron Transport Chain Complex Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012402:Rotenone; D003900:Desoxycorticosterone; D011374:Progesterone; D000968:Antimycin A; D014700:Verapamil; D000251:Adenosine Triphosphatases; C070272:valspodar
keywords: ABCB1; Collateral sensitivity; Desoxycorticosterone; Drug resistance; P-glycoprotein; Progesterone