Sensitizing human multiple myeloma cells to the proteasome inhibitor bortezomib by novel curcumin analogs

Abstract

The proteasome plays a vital role in the degradation of proteins involved in several pathways including the cell cycle, cellular proliferation and apoptosis and is a validated target in cancer treatment. Bortezomib (Velcade®, PS-341) is the first US FDA approved proteasome inhibitor anticancer drug used in the treatment of refractory multiple myeloma. In spite of its improved efficacy compared to alternative therapies, about 60% of patients do not respond to bortezomib due to the emergence of resistance. We hypothesized that novel small molecules could enhance the proteasome-inhibitory and anticancer activities of bortezomib in resistant multiple myeloma cells in vitro and in vivo. The dietary polyphenol curcumin has been shown to exert anti-cancer activity in several cancer cell lines, but the effects of curcumin in solid tumors have been modest primarily due to poor water solubility and poor bioavailability in tissues remote from the gastrointestinal tract. Here we show that the water-soluble analog of curcumin #12, but not curcumin, in combination with bortezomib could enhance the proteasome-inhibitory effect in multiple myeloma cells. Furthermore, the sensitivity of the myeloma cells to cytotoxic killing in the presence of otherwise sublethal concentrations of bortezomib was enhanced by incubation with the curcumin analog #12. These findings justify further investigation into those combinations that may yield potential therapeutic benefit.

Curcumin Enhances Cytotoxic Effects of Bortezomib in Human Multiple Myeloma H929 Cells: Potential Roles of NF-κB/JNK

“…IκB, NF-κB p65, JNK and p-JNK protein contents in response to various treatments were determined by Western blot as described previously [ 14 – 17 ].…”

“…Interestingly, it is noted that curcumin shows a synergistic effect when combined with PS-341. We and others have recently reported that curcumin enhances the cytotoxic effect of PS-341 in human multiple myeloma cells through regulating NF-κB and Bcl-2 family proteins expressions [ 14 – 17 ]. These beneficial merits develop curcumin as a potential adjuvant agent to standard chemotherapy, in particular for highly malignant, refractory, and relapsed cancers.…”

Mechanism insights of curcumin and its analogues in cancer: An update

“…Cell proteasome activities CT‐like, trypsin‐like, and PGPH were adversely affected. This blend also brings about an extensive increment in caspase movement, which could induce apoptosis in these cells (Mujtaba et al, 2012). These findings have paved the way for several exciting clinical and pre‐clinical studies of the proteasome as a target for cancer therapy.…”

Synergistically Anti-Multiple Myeloma Effects: Flavonoid, Non-Flavonoid Polyphenols, and Bortezomib

“…Notably, similar to curcumin, the twelfth curcumin analog increased PARP and caspase-3 cleavage, enhancing BTZ-induced apoptosis. The water-soluble, highly bioavailable twelfth curcumin analog has the potential to replace curcumin in anti-MM therapy in the future [ 40 ].…”