Inhibition of aldehyde dehydrogenase-1 and p-glycoprotein-mediated multidrug resistance by curcumin and vitamin D3 increases sensitivity to paclitaxel in breast cancer.

Autor: Attia YM; Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt. Electronic address: yasmeen.attia@bue.edu.eg., El-Kersh DM; Pharmacognosy Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Ammar RA; Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Adel A; Senior Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Khalil A; Senior Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Walid H; Senior Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Eskander K; Senior Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Hamdy M; Senior Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Reda N; Senior Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Mohsen NE; Senior Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Al-Toukhy GM; Virology and Immunology Department, Children's Cancer Hospital, 57357, Cairo, Egypt., Mansour MT; Virology and Immunology Department, Children's Cancer Hospital, 57357, Cairo, Egypt; Virology and Immunology Department, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt., Elmazar MM; Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2020 Jan 05; Vol. 315, pp. 108865. Date of Electronic Publication: 2019 Oct 16.
DOI: 10.1016/j.cbi.2019.108865
Abstrakt: Treatment of breast cancer by paclitaxel (PAX) often encounters therapeutic failure most likely caused by innate/acquired resistance. Cancer stem cells (CSCs) and multidrug resistance complex (MDR-1 or P-glycoprotein) overexpression are main mechanisms implicated in chemoresistance. Increased aldehyde dehrogenase-1 (ALDH-1) was previously correlated with the stemness features of CSCs and hence is used as a marker for identification and CSCs targeting. The present study, therefore, aimed at investigating the effect of both curcumin (CUR) and vitamin D3 (D3) on MDR-1 and ALDH-1 expression and consequently the resistance to PAX both in vitro and in vivo. CUR was isolated from Turmeric rhizomes and identified using UPLC-ESI-MS/MS. For in vitro studies, the antiproliferative effect of PAX, CUR, 1,25(OH)2D3 (the active form of D3, also known as calcitriol) was determined, each alone and combined (PAX+CUR, PAX+1,25(OH)2D3, and PAX+CUR+1,25(OH)2D3) on MCF-7 breast cancer cells. Ehrlich ascites carcinoma solid tumor animal model was also used for in vivo studies. Combining CUR and/or 1,25(OH)2D3 to PAX showed synergistic cytotoxic interaction on MCF-7 cells. The apoptotic potential was also enhanced, as evidenced by a significant increase in caspase-7 and -9 as well as the pro-apoptotic Bax whereas a decrease in Bcl-2 levels was reported. Combining CUR and 1,25(OH)2D3 to PAX caused a downregulation in both MDR-1 and ALDH-1 gene expression in MCF-7 besides a decrease in their protein levels. In vivo, the triple therapy group (PAX+CUR+D3) showed the least tumor size. It also showed the lowest levels of MDR-1 and ALDH-1. PAX alone, however, showed increased levels of MDR-1 and ALDH-1 compared to control. Overall, the present study showed that PAX, as a monotherapy, demonstrated acquired resistance possibly by increasing MDR-1 expression and enriching CSCs population, as evidenced by increased ALDH-1. However, using CUR and D3 enhanced tumor response to PAX.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2019 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE