A novel life for antitumor combretastatins: Recent developments of hybrids, prodrugs, combination therapies, and antibody-drug conjugates

Since their discovery from natural sources, the potent cytotoxic effects of combretastatins were widely studied for the application in antitumor therapy. However, major pharmacokinetic issues as low water solubility and chemical instability of the double bond configuration prevented their use in therapy. A lot of efforts have been directed towards the search of novel strategies, allowing a safer use of combretastatins as anticancer agents. This review analyses the recent landscape in combretastatin research, characterized by the identification of hybrids, prodrugs, and novel combination treatments. Interestingly, the potent cytotoxic agent combretastatin A4 (CA4) was recently proposed as payload in the construction of novel antibody-drug conjugates (ADCs), allowing an efficient targeting of the cytotoxic agent to specific tumors.