Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo.

Cisplatin-based therapy is one of the most important chemotherapy treatments for cancers. However, its efficacy is greatly limited by drug resistance and undesirable side effects. Therefore, it is of great importance to develop effective chemosensitization agents to cisplatin. In the present study, we demonstrated the strategy to use shikonin, a natural product from the root of Lithospermum erythrorhizon, as a synergistic agent of cisplatin and elucidated their action mechanisms. The combination of shikonin and cisplatin exhibited synergistic anticancer efficacy and achieved greater selectivity between cancer cells and normal cells. By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway. In addition, inhibition of ROS reversed the apoptosis induced by shikonin and cisplatin, and recovered the depletion of mitochondrial membrane potential, which revealed the vital role of ROS in the synergism. Moreover, HCT116 xenograft tumor growth in nude mice was more effectively inhibited by combined treatment with shikonin and cisplatin. Our findings suggest that the strategy to apply shikonin as a synergistic agent to cisplatin could be a highly efficient way to achieve anticancer synergism by inducing intracellular oxidative stress. Shikonin may be a promising candidate as a chemosensitizer to cisplatin-based therapy for cancer treatments.