Effects of Epirubicin and Cisplatin Against 4T1 Breast Cancer Cells are Enhanced by Myrtucommulone-A.

BACKGROUND: The number of cancer cases around the world has increased according to the World Health Organization (WHO) reports, nearly 14 million new cases and 8.2 million cancer associated mortalities have been reported in 2012. Chemotherapeutic resistance is a major problematic issue in the management of patients with breast tumor. OBJECTIVE: In this study, the apoptotic gene profile of 4T1 mouse breast cancer cells treated with MC-A in combination with cisplatin or epirubicin was evaluated to decipher the possible apoptotic molecular targets. METHODS: The effects of MC-A in combination with cisplatin (CIS) or epirubicin (EPI) on cytotoxicity, cell migration, wound healing, clonogenicity along with enhanced effect of these combinations on 84 apoptosis related genes were tested in 4T1 cancer cells. RESULTS: MC-A in combination with epirubicin or cisplatin robustly induced cytotoxicity in 4T1 cells in vitro. MC-A in combination with cisplatin or epirubicin showed significantly inhibition of cell migration compared to treatment with each agent alone. Genes involved in positive regulation of apoptosis, negative regulator of apoptosis, death-like, mitochondrial apoptotic signaling, induction of apoptosis through DR3 and DR4/5 death receptors, and anti-apoptosis were highly affected in MC-A+cisplatin or MC-A+epirubicin combinations compared to each agent only. CONCLUSIONS: In conclusion, the apoptotic response of 4T1 cancer cells to chemotherapeutic drugs occurs in different ways. MC-A in combination with these chemotherapeutic drugs could modulate the expression of genes involved in both extrinsic and intrinsic pathways of apoptosis, leading to higly effective apoptotic signalling in cancer treatment.

Inhibition of epithelial-mesenchymal transition in bladder cancer cells via modulation of mTOR signalling.

Mounting evidence suggests that signalling cross-talk plays a significant role in the regulation of epithelial-mesenchymal transition (EMT) in cancer cells. However, the complex network regulating the EMT in different cancer types has not been fully described yet which affects the development of novel therapeutic strategies. In the present study, we investigated the signalling pathways involved in EMT of bladder cancer cells and demonstrated the effects of two novel agents in the regulation of EMT. Myrtucommulone-A (MC-A) and thymoquinone (TQ) have been shown to possess anti-cancer properties. However, their targets in the regulation of cancer cell behavior are not well defined. Here, we defined the effects of two putative anti-cancer agents on bladder cancer cell migration and their possible intracellular targets in the regulation of EMT. Our results suggest that MC-A or TQ treatment affected N-cadherin, Snail, Slug, and ß-catenin expressions and effectively attenuated mTOR activity. The downstream components in mTOR signalling were also affected. MC-A treatment resulted in the concomitant inhibition of extracellular matrix-regulated protein kinases 1 and 2 (ERK 1/2), p38 mitogen-activated protein kinase (MAPK) and Src activity. On the other hand, TQ treatment increased Src activity while exerting no effect on ERK 1/2 or p38 MAPK activity. Given the stronger inhibition of EMT-related markers in MC-A-treated samples, we concluded that this effect might be due to collective inhibition of multiple signalling pathways which result in a decrease in their cross-talk in bladder cancer cells. Overall, the data in this study proposes novel action mechanisms for MC-A or TQ in bladder cancer cells and highlights the potential use of these active compounds in the regulation of EMT.