Resveratrol selectively induces apoptosis in malignant cells with the JAK2V617F mutation by inhibiting the JAK2 pathway.

Scope: Resveratrol is a natural occurring polyphenol with several health promoting activities, including anticancer potential. Here, we analyzed the cytotoxic effects of resveratrol against malignant cells characterized by aberrant activation of the Janus kinase 2 (JAK2).

Methods And Results: Cell-cycle analysis, proliferation, apoptosis, and Western blotting assays were performed to study the effect of resveratrol on malignant cells exhibiting an excessive activation of the JAK2 pathway secondary to the JAK2(V617F) mutation. Resveratrol inhibited proliferation and induced apoptosis in JAK2(V617F) mutant tumor cells and its selectivity was 1.5-6.9 times greater than that observed in other tumor cells without the JAK2(V617F) mutation. In addition, resveratrol inhibited the phosphorylation of JAK1, JAK2, and Tyk2 and their downstream mediators, including STAT3 and STAT5. In primary cultures, resveratrol treatment inhibited erythroid progenitor colony formation in blood samples obtained from JAK2(V617F) polycythemia vera patients. Moreover, resveratrol synergized with the selective JAK2 inhibitor ruxolitinib, eliminating tumor cells with the JAK2 mutation.

Conclusion: Resveratrol may have therapeutic potential against myeloproliferative neoplasms associated with the aberrant activation of the JAK2 pathway.