title: Inhibition of ALDH1A1 activity decreases expression of drug transporters and reduces chemotherapy resistance in ovarian cancer cell lines.
abstract: The high mortality of ovarian cancer patients results from the failure of treatment caused by the inherent or acquired chemotherapy drug resistance. It was reported that overexpression of aldehyde dehydrogenase A1 (ALDH1A1) in cancer cells can be responsible for the development of drug resistance. To add the high expression of the drug transporter proteins the ALDHA1 is considered as a molecular target in cancer therapy. Therefore, we analysed drug-resistant ovarian cancer cell lines according to ALDHA1 expression and the association with drug resistance. The expression of ALDH1A1, P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) was determined using a microarray and confirmed by Q-PCR, western blot and fluorescence analysis. ALDH1A1 activity was determined using an Aldefluor assay. The impact of all-trans retinoic acid (ATRA) and diethylaminobenzaldehyde (DEAB) on chemotherapy resistance was assessed by the MTT chemosensitivity assay. The most abundant expression of ALDH1A1 was noted in paclitaxel- and topotecan-resistant cell lines where two populations of ALDH-positive and ALDH-negative cells could be observed. Those cell lines also revealed the overexpression of P-gp and BCRP respectively, and were able to form spheres in non-adherent conditions. Pre-treatment with ATRA and DEAB reduced chemotherapy resistance in both cell lines. ATRA treatment led to downregulation of the ALDH1A1, P-gp and BCRP proteins. DEAB treatment led to downregulation of the P-gp protein and BCRP transcript and protein. Our results indicate that ALDH1A1-positive cancer cells can be responsible for drug resistance development in ovarian cancer. Developing more specific ALDH1A1 inhibitors can increase chemotherapy effectiveness in ovarian cancer.
authors.affiliation: Department of Histology and Embryology, Poznaſ University of Medical Sciences, Poland. Electronic address: rjanuchowski@ump.edu.pl.
authors.forename: Radosſaw
authors.initials: R
authors.lastname: Januchowski
authors.affiliation: Department of Histology and Embryology, Poznaſ University of Medical Sciences, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wojtowicz
authors.affiliation: Department of Histology and Embryology, Poznaſ University of Medical Sciences, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Sterzyſska
authors.affiliation: Department of Pathophysiology, Poznaſ University of Medical Sciences, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Sosiſska
authors.affiliation: Department of Histology and Embryology, Poznaſ University of Medical Sciences, Poland.
authors.forename: Maſgorzata
authors.initials: M
authors.lastname: Andrzejewska
authors.affiliation: Department of Histology and Embryology, Poznaſ University of Medical Sciences, Poland; Department of Anatomy, Poznaſ University of Medical Sciences, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Zawierucha
authors.affiliation: Department of Histology and Embryology, Poznaſ University of Medical Sciences, Poland.
authors.forename: Michaſ
authors.initials: M
authors.lastname: Nowicki
authors.affiliation: Department of Histology and Embryology, Poznaſ University of Medical Sciences, Poland; Department of Histology and Embryology, Wroclaw Medical University, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Zabel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000970:Antineoplastic Agents / Q000494:pharmacology; D001547:Benzaldehydes / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000473:pathology*; D050697:Retinal Dehydrogenase; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; C055506:4-(diethylamino)benzaldehyde; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: Aldehyde dehydrogenase 1A1; Anticancer therapy; Drug resistance; Drug transporters; Ovarian cancer stem cells