Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways

Abstract

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.

Molecular mechanisms of suberoylanilide hydroxamic acid in the inhibition of TGF‐β1‐mediated canine corneal fibrosis

“…However, SAHA did not affect the phosphorylation of p38 MAPK or JNK1, suggesting that these two MAPKs are not involved in the anti‐fibrotic mechanisms of SAHA in the cornea. These results conflict with those of previous studies which demonstrated the ability of HDACi, including SAHA, to inhibit phosphorylation of p38 MAPK in neoplastic cells, rheumatoid arthritis synovial fibroblast, and lens epithelial cells . It is important to note that these studies utilized cytokines different than TGF‐β1 to induce cellular transformation and fibrosis.…”

Oxidative stress and proteasome inhibitors in multiple myeloma

“…LBH589 has been recently approved for treatment of patients with relapsed and refractory multiple myeloma [80]. Although several mechanisms have been proposed for LBH589-dependent generation of ROS [93-95], it is worth noting that KLF9 has been reported by us previously to mediate LBH589 cytotoxicity in multiple myeloma cells [81] and thus could account, at least in part, for the LBH-dependent oxidative stress in these cells. Several other histone deacetylase inhibitors cooperated or synergized with BTZ in inducing oxidative stress and apoptosis in multiple myeloma cells in vitro , including sodium butyrate and suberoylanilide hydroxamic acid [95], PXD101 (belinostat, Beleodaq), [96], and KD5170 [97].…”

Role of p38 MAPK activation and mitochondrial cytochrome-c release in allicin-induced apoptosis in SK-N-SH cells

“…The MAPK signaling pathway plays important roles in regulating apoptosis induced by various cellular stresses and chemotherapeutic agents [34,35]. However, the detailed mechanisms of these pathways in cell death remain elusive.…”