Patients with advanced
prostate cancer (PCa) and
multiple myeloma (MM) have limited long-term responses to available
therapies. The
histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid
malignancies and is currently in phase III trials for relapsed MM.
Bisphosphonates (BPs), such as
zoledronic acid (ZOL), inhibit osteoclast-mediated
bone resorption and are indicated for the treatment of bone
metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of
panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status,
androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent
agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the
antioxidant N-acetyl-L-cysteine blocked the increased
reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-
geraniol, which bypasses the inhibition of
farnesylpyrophosphate synthase by ZOL in the
mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by
panobinostat in sensitive and ZOL-resistant cells and in
tumor xenografts could explain, at least in part, the observed synergism.