Exploring Cantharidin and its Analogues as Anticancer Agents: A Review

Background: Cantharidin (CTD) is a highly toxic substance which can be used to treat a variety of cancers. However, the clinical application of CTD is restricted due to the serious side effects. In recent years, screening its analogues, exploring the mechanism of action and using combinatory therapy with certain substances are considered to be feasible methods which can reduce side effects and improve the therapeutic activity of CTD. This review aims to describe SAR (structure-activity relationship) of CTD analogues, CTD induction mechanisms, and combinatory therapy exploration. Methods: We searched for research about CTD by entering the database. Important information was screened and extracted purposefully, including SAR, mechanisms, methods, etc. Finally, these contents were unified into a framework to form a review. Results: Some CTD analogues with imidazolium salt or double bonds at C-5 and C-6 positions demonstrate good anticancer activity. Through introducing methyl and acetoxy groups at the C-1 or C-4 position, the inhibitory effect of PP was weakened or even inactivated. Removing the two methyl groups of C-2 and C-3 can reduce side effects and improve efficacy. Replacing methyl with fluorine can also improve the activity and reduce toxicity. Water solubility and bioavailability could be improved by opening the five fivemembered anhydride ring to form carboxylic acid, salt, amide, and ester derivatives. The anticancer mechanism can be divided into the following aspects, including inhibiting cell invasion and metastasis, inducing apoptosis, regulating cell cycle and enhancing immunity. The proper formulation of CTD and its analogues (liposomes, nanoparticles and micelles) can improve the targeting of liver cancer and reduce toxic and side effects. CTD combined with anti-angiogenic therapeutics (Ginsenoside Rg3, Bevacizumab, Apatinib and Endostar) showed additive anti-pancreatic cancer effects. Conclusion: It was found that the potential mechanism was closely related to multi-channel and multi-target interactions, which provided a guiding direction for the later exploration of new clinical therapeutic applications. However, some detailed mechanisms are still unclear, and more evidence is required to verify. In addition, the new methods to improve the therapeutic potential of CTD and its analogues still need more clinical trials to be tested in the future. This prospect is very broad and worthy of further study.