Thymoquinone and Costunolide Induce Extensive Apoptosis of Senescent Colon and Senescent Breast Cancer Cells

Abstract

Several chemotherapeutic agents induce cancer cells’ senescence as monitored by enlargement of cell, cell cycle arrest, elevated activities of senescence-associated β-galactosidase (SA-β-gal), and upregulation of p53 and p21. Doxorubicin (Dox) is an anticancer chemotherapeutic drug, classified as an anthracycline antibiotic, that induces senescence of numerous cancer cell types. The arrest of cancer cell growth is a bright face of senescence, while these senescent cancer cells relapse again if they are not eliminated. On this principle, we investigated the apoptotic effect of thymoquinone (TQ), the active ingredient of Nigella sativa seeds and costunolide (COS), the active ingredient of Costus speciosus, on senescent colon (Sen-HCT116) and senescent breast (Sen-MCF7) cancer cell lines in reference to their corresponding proliferative cells to rapidly eliminate the senescent cancer cells. The senescence markers of Sen-HCT116 and Sen-MCF7 were determined by significant decrease in bromodeoxyuridine (BrdU) incorporation and significant increases in SA-β-gal, p53, and p21 levels. After proliferative, Sen-HCT116, and Sen-MCF7 cells were subjected to either TQ (50 µM) or COS (30 µM), the Bcl2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), and their ratio were established. Results revealed that TQ significantly increased the Bax/Bcl2 ratio in HCT116+Dox5+TQ, MCF7+TQ, and MCF7+Dox5+TQ compared with their corresponding controls. COS significantly increased the Bax/Bcl2 ratio in HCT116+Dox5+TQ and MCF7+Dox5+TQ compared with their corresponding controls. The data revealed more sensitivity of senescent cells to TQ or COS than their corresponding proliferative cells. Thus, we may be able to use TQ or COS to rapidly eliminate senescent cancer cells following Dox treatment; these results need to be confirmed with in vivo and clinical trials.