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Several sesquiterpene lactones have been extracted and demonstrated to exert various pharmacological functions in a variety of cancers. Here, we investigated anti-tumor effect of alantolactone, an allergenic sesquiterpene lactone, on human multiple myeloma (MM) and showed alantolactone inhibited growth of MM cells, both in the presence or absence of bone marrow (BM)-derived stromal cells (HS-5), and subsequent G1 phase arrest, and apoptosis as demonstrated by increased Annexin-V/7-AAD binding, caspase-3 or caspase-9 activation and down-modulation of activation of extracellular signal-regulated kinases 1/2. In addition, alantolactone reduced the secretion of MM survival and growth-related cytokines, vascular endothelial growth factor, from MM cells or HS-5 cells, and inhibited cytokine-induced osteoclastogenesis. Notably, alantolactone also inhibited cell proliferation in bortezomib-resistant MM cells. Taken together, alantolactone exerted anti-tumor effect on MM by suppressing cell proliferation, triggering apoptosis, partly damaging the BM microenvironment and overcoming proteasome inhibitor resistance, suggesting alantolactone may be a novel therapeutic approach for the treatment of human MM.

Effective new therapies are urgently needed for the treatment of multiple myeloma (MM), an incurable hematological malignancy. In this study, we evaluated the effects of piperlongumine on MM cell proliferation both in vivo and in vitro. Piperlongumine inhibited the proliferation of MM cells by inducing cell apoptosis and blocking osteoclastogenesis. Notably, piperlongumine also reduced bortezomib resistance in MM cells. In a disseminated MM mouse model, piperlongumine prolonged the survival of tumor-bearing mice without causing any obvious toxicity. Mechanistically, piperlongumine inhibited the STAT3 signal pathway in MM cells by binding directly to the STAT3 Cys712 residue. These findings suggest that the clinical use of piperlongumine to overcome bortezomib resistance in MM should be evaluated.