A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

Abstract

Abstract. Renal cell carcinoma (RCC) is resistant to traditional cancer therapies such as radiation therapy and chemotherapy. The use of targeted therapies has improved the clinical outcomes of patients with metastatic RCC. However, most patients acquire resistance against targeted therapies over time. We report that the combination of the novel histone deacetylase (HDAC) inhibitor OBP-801, also known as YM753 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 synergistically inhibits cell growth and induces apoptosis in RCC cells. This combination activated caspase-3, -8 and -9 and the pan-caspase inhibitor zVAD-fmk significantly reduced the apoptotic response to the treatment with OBP-801 and LY294002. Moreover, the combined treatment induced intracellular reactive oxygen species (ROS) and the radical scavenger N-acetyl-L-cysteine (NAC) blocked the intracellular ROS and apoptosis induced by OBP-801 and LY294002. The co-treatment with OBP-801 and LY294002 markedly decreased survivin and the X-linked inhibitor of apoptosis protein (XIAP) protein levels, but Bcl-2 family members were not altered by the OBP-801/LY294002 co-treatment. These alterations were restored by NAC treatment. The transient transfection of survivin and XIAP reduced the apoptotic response to the OBP-801/LY294002 co-treatment. Additionally, OBP-801 was significantly more effective than SAHA, another HDAC inhibitor, in the combination with LY294002 against 786-O cells. Taken together, these results strongly suggest the combination of OBP-801 and LY294002 to be a promising treatment for RCC.

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

“…We expected that OBP-801 known to suppress survivin [10,11] was an appropriate agent for the combination with eribulin when eribulin was proved to upregulate survivin in TNBC like other microtubule dynamics inhibitors [12]. Our findings showed that the combination treatment of OBP-801 and eribulin induced the synergistic growth inhibition of TNBC cells through apoptosis with the suppression of Bcl-xL and the MAPK pathway as well as survivin.…”

Sevoflurane suppresses hypoxia-induced growth and metastasis of lung cancer cells via inhibiting hypoxia-inducible factor-1α

“…XIAP and survivin are the most potent caspase inhibitors of all of the IAPs. They can block the intrinsic and extrinsic apoptosis pathways via binding to caspases 3, 7, and 9 [25,26]. The expressions of XIAP and survivin are dramatically up-regulated in many cancers, resulting in a poor prognosis for cancer patients [27].…”

Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

“…However, the frequency of mutations in TSC1 has proven to be low [33, 51]. Therefore other mechanisms preventing mTORC1 inhibition by REDD1 are to be determined.…”