Inhibition of ALDH1A1 activity decreases expression of drug transporters and reduces chemotherapy resistance in ovarian cancer cell lines. (September 2016)

• Record Type: Journal Article
• Authors: Januchowski, Radosſaw; Wojtowicz, Karolina; Sterzyſska, Karolina; Sosiſska, Patrycja; Andrzejewska, Maſgorzata; Zawierucha, Piotr; Nowicki, Michaſ; Zabel, Maciej
• Is Part Of: International journal of biochemistry & cell biology. Volume 78(2016:Sep.)
• Page Start: 248
• Page End: 259
• Publication Date: 2016-09
• Subjects: ALDH1A1 Aldehyde dehydrogenase 1A1 -- P-gp P-glycoprotein -- BCRP breast cancer resistance protein -- ATRA all-trans retinoic acid -- DEAB diethylaminobenzoaldehyde -- PAC paclitaxel -- TOP topotecan -- CIS cisplatin -- DOX doxorubicin -- MDR multiple drug resistance -- RA retinoid acid -- NSCs normal stem cells -- SCSs cancer stem cells -- 4-HC 4-hydroperoxycyclophosphamide -- APL acute promyelocytic leukaemia -- MTX methotrexate -- VIN vincristine -- GADPH glyceraldehyde-3-phospate dehydrogenase -- HRPT1 hypoxanthine-guanine phosphoribosyltransferase 1 -- β2M beta-2-microglobulin -- RQ relative quantification -- ECL enhanced cgemical luminescence -- CS-like stem cell-like -- NSCLC non-small cell lung cancer; Aldehyde dehydrogenase 1A1 -- Drug resistance -- Ovarian cancer stem cells -- Anticancer therapy -- Drug transporters; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2016.07.017
• Languages: English
• ISSNs: 1357-2725

Abstract

Highlights: ⿢ High expression of ALDH1A1 was observed in paclitaxel and topotecan- resistant cancer cell lines. ⿢ Pretreatment with ATRA and DEAB reduced chemotherapy resistance in investigated cell lines. ⿢ ATRA treatment led to downregulation of ALDH1A1, P-gp and BCRP proteins. ⿢ DEAB treatment led to downregulation of P-gp and BCRP proteins. 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.