Abstract
Ceramide (CE)-based combination therapy (CE combination) as a novel therapeutic strategy has attracted great attention in the field of anti-cancer therapy. The principal purposes of this study were to investigate the synergistic effect of CE in combination with docetaxel (DTX) (CE + DTX) and to explore the synergy mechanisms of CE + DTX. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and combination index (CI) assay showed that simultaneous administration of CE and DTX with a molar ratio of 0.5:1 could generate the optimal synergistic effect on murine malignant melanoma cell (B16, CI = 0.31) and human breast carcinoma cell (MCF-7, CI = 0.48). The apoptosis, cell cycle, and cytoskeleton destruction study demonstrated that CE could target and destruct the microfilament actin, subsequently activate Caspase-3 and induce apoptosis. Meanwhile, DTX could target and disrupt the microtubules cytoskeleton, leading to a high proportion of cancer cells in G2/M-phase arrest. Moreover, CE plus DTX could cause a synergistic destruction of cytoskeleton, which resulted in a significantly higher apoptosis and a significantly higher arrest in G2/M arrest comparing with either agent alone (p < 0.01). The in vivo antitumor study evaluated in B16 tumor-bearing mice also validated the synergistic effects. All these results suggested that CE could enhance the antitumor activity of DTX in a synergistic manner, which suggest promising application prospects of CE + DTX combination treatment.
Highlights
Cancer is the leading cause of deaths worldwide and chemotherapy is one of the major trends on cancer therapy [1,2]
In spite of moderate increase in the therapeutic efficacy, combining multiple cytotoxic drugs for cancer therapy might simultaneously lead to a potential danger of drug interaction toxicity [10], cross-resistance [11]
The anti-proliferation effects of CE combination (CE + DTX, CE + PTX, or CE + DOX) at molar ratio 1:1 was evaluated at various concentrations by MTT assay on B16, SKOV3, MCF-7, and HepG2 cells, respectively
Summary
Cancer is the leading cause of deaths worldwide and chemotherapy is one of the major trends on cancer therapy [1,2]. The problems of mono-chemotherapy, such as inadequacy of efficacy, drug resistance and systemic toxicity, would not be completely solved in a short time. The administration doses of cytotoxic drugs cannot be limitlessly increased [3]. Based on this situation, combination therapy arose in response and was expected to achieve high therapeutic efficacy at lower drug dose [4]. Among various kinds of combination therapy strategies, combinations of multiple cytotoxic drugs have attracted significant attention [3]. In spite of moderate increase in the therapeutic efficacy, combining multiple cytotoxic drugs for cancer therapy might simultaneously lead to a potential danger of drug interaction toxicity [10], cross-resistance [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
