Enhanced in vivo targeting of estrogen receptor alpha signaling in murine mammary adenocarcinoma by nilotinib/rosuvastatin novel combination.
The development of resistance to endocrine therapy of estrogen receptor alpha (ERα)-positive breast cancer is inevitable, necessitating the introduction of alternative treatment strategies. Therefore, the current study was carried out to investigate the in vivo efficacy and tolerability of nilotinib/rosuvastatin novel combination against ERα-positive breast carcinoma. Results showed that treatment of tumor-bearing mice with nilotinib/rosuvastatin exerted a significant antitumor activity. Mechanistically, the combination treatment efficiently inhibited the in vivo ERα protein expression, whereas ERα mRNA levels were unaffected suggesting a posttranslational regulation. In addition, the combination treatment markedly downregulated the expression of two ERα downstream target genes: C3 and pS2 confirming the inhibition of ERα signaling in vivo. Further, nilotinib/rosuvastatin combination strongly induced apoptosis evidenced by a marked caspase-3 cleavage and downregulation of tumor nitric oxide levels. Moreover, histopathology showed significant declines in mitotic figures and tumor giant cells implying the in vivo capability of the combination treatment to interfere with cancer cell proliferation and persistence. Of note, the combination treatment abrogated nilotinib-induced hypercholesterolemia and did not adversely affect the liver function or body weight. Overall, the present study provided evidences that warrant further assessment of nilotinib/rosuvastatin combination as an alternative therapeutic modality for ERα-positive breast cancer.
['Goda|Ahmed E|AE|', 'Elsisi|Alaa E|AE|', 'Sokkar|Samia S|SS|', 'Abdelrazik|Noha M|NM|']
D000230:Adenocarcinoma D000818:Animals D000970:Antineoplastic Agents D004305:Dose-Response Relationship, Drug D004359:Drug Therapy, Combination D047628:Estrogen Receptor alpha D005260:Female D015972:Gene Expression Regulation, Neoplastic D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors D015674:Mammary Neoplasms, Animal D008325:Mammary Neoplasms, Experimental D051379:Mice D011743:Pyrimidines D000068718:Rosuvastatin Calcium
Estrogen receptor alpha Nilotinib Rosuvastatin Breast cancer Apoptosis