Mitochondrial targeting derivatives of honokiol enhanced selective antitumor activity in NCI-H446 cells and decreased in vivo toxicity in Caenorhabditis elegans.

Mitochondria, responsible for ATP production and apoptosis regulation, play a key role in cancer cells. Honokiol regulates apoptosis through the endogenous mitochondrial pathway but does not specifically target tumor cells. We designed 28 novel derivatives of honokiol using triple-function delocalized lipophilic cations such as berberine and F16 as mitochondrion-targeting carriers. While all derivatives exhibited enhanced cytotoxicity toward tumor cells compared to honokiol, the derivative 2E-3-F16 exhibited a substantial tumor cell selectivity between NCI-H446 cancer cells and HBE cells by one order of magnitude and enhanced the sensitivity of A549 cells to cisplatin. Mechanistically, it targeted mitochondria and induced apoptosis by preventing tumor cells from entering the G0/G1 phases as well as inducing an abnormal elevation of reactive oxygen species, thereby decreasing the mitochondrial membrane potential level. It also showed lower toxicity toward Caenorhabditis elegans than honokiol. This study provides a possible method for developing mitochondrion-targeting antitumor drugs with high efficiency and low toxicity based on natural products.