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

Authors

Yasmeen M. Attia, The British University in EgyptFollow
Dina M. El-Kersh, The British University in EgyptFollow
Reham A. Ammar, The British University in Egypt
Aliaa Adel, The British University in Egypt
Aya Khalil, The British University in Egypt
Hoda Walid, The British University in Egypt
Kirullos Eskander, The British University in Egypt
Mohamed Hamdy, The British University in Egypt
Nada Reda, The British University in Egypt
Nour Elhoda Mohsen, The British University in Egypt
Ghada M. Al-Toukhy, Children's Cancer Hospital 57357
Mohamed Tarek Mansour, Children's Cancer Hospital 57357
Mohamed M. Elmazar, The British University in EgyptFollow

Document Type

Article

Publication Date

1-5-2020

Abstract

© 2019 Elsevier B.V. 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.

Recommended Citation

Attia, Yasmeen M.; El-Kersh, Dina M.; Ammar, Reham A.; Adel, Aliaa; Khalil, Aya; Walid, Hoda; Eskander, Kirullos; Hamdy, Mohamed; Reda, Nada; Mohsen, Nour Elhoda; Al-Toukhy, Ghada M.; Mansour, Mohamed Tarek; and Elmazar, Mohamed M., "Inhibition of aldehyde dehydrogenase-1 and p-glycoprotein-mediated multidrug resistance by curcumin and vitamin D3 increases sensitivity to paclitaxel in breast cancer" (2020). Pharmacy. 194.
https://buescholar.bue.edu.eg/pharmacy/194