Polyphenolic Boronates Inhibit Tumor Cell Proliferation: Potential Mitigators of Oxidants in the Tumor Microenvironment

SIMPLE SUMMARY: Several plant-based compounds inhibit tumor cell growth. Selective modification of these compounds significantly increases their antitumor potency. The goal of this study was to develop less toxic, more potent natural compounds for use in cancer and immune therapies. To this end, we modified the structures of honokiol and magnolol, the two active components of magnolia extract. The modified compounds—honokiol boronate and mitochondria-targeted honokiol boronate—target the mitochondria of tumor cells and inhibit cell proliferation. These boronate derivatives also react with oxidants that are generated in tumor mitochondria and the tumor microenvironment. During this process, these boronate derivatives are also converted back to the original compounds with antitumor potencies. Thus, boronation of naturally occurring plant-derived compounds could make them more active in tumor cells as well as in the adjoining tumor microenvironment. These novel polyphenolic derivatives may enhance the scope of cancer immunotherapies. ABSTRACT: Boronate-based compounds have been used in brain cancer therapy, either as prodrugs or in combination with other modalities. Boronates containing pro-luminescent and fluorescent probes have been used in mouse models of cancer. In this study, we synthesized and developed polyphenolic boronates and mitochondria-targeted polyphenolic phytochemicals (e.g., magnolol [MGN] and honokiol [HNK]) and tested their antiproliferative effects in brain cancer cells. Results show that mitochondria-targeted (Mito) polyphenolic boronates (Mito-MGN-B and Mito-HNK-B) were slightly more potent than Mito-MGN and Mito-HNK in inhibiting proliferation of the U87MG cell line. Similar proliferation results also were observed in other cancer cell lines, such as MiaPaCa-2, A549 and UACC-62. Independent in vitro experiments indicated that reactive nitrogen species (e.g., peroxynitrite) and reactive oxygen species (e.g., hydrogen peroxide) stoichiometrically react with polyphenolic boronates and Mito-polphenolic boronates, forming polyphenols and Mito-polyphenols as major products. Previous reports suggest that both Mito-MGN and Mito-HNK activate cytotoxic T cells and inhibit immunosuppressive immune cells. We propose that Mito-polyphenolic boronate-based prodrugs may be used to inhibit tumor proliferation and mitigate oxidant formation in the tumor microenvironment, thereby generating Mito-polyphenols in situ, as well as showing activity in the tumor microenvironment.