A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance

Abstract

Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells. Three pancreatic cancer-cell lines were used to evaluate the antitumor effect of CG200745 combined with gemcitabine/erlotinib. CG200745 induced the expression of apoptotic proteins (PARP and caspase-3) and increased the levels of acetylated histone H3. CG200745 with gemcitabine/erlotinib showed significant growth inhibition and synergistic antitumor effects in vitro. In vivo, gemcitabine/erlotinib and CG200745 reduced tumor size up to 50%. CG200745 enhanced the sensitivity of gemcitabine-resistant pancreatic cancer cells to gemcitabine, and decreased the level of ATP-binding cassette-transporter genes, especially multidrug resistance protein 3 (MRP3) and MRP4. The novel HDAC inhibitor, CG200745, with gemcitabine/erlotinib had a synergistic anti-tumor effect on pancreatic cancer cells. CG200745 significantly improved pancreatic cancer sensitivity to gemcitabine, with a prominent antitumor effect on gemcitabine-resistant pancreatic cancer cells. Therefore, improved clinical outcome is expected in the future.

HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment

“…These contradictory effects might reflect the distinct roles of individual HDACs in the immune responses. Therefore, the novel discovery of CG-745 in anti-cancer immunity suggests an excellent combination partner of various cancer immunotherapy and supports the reason why CG-745 shows the excellent synergistic efficacy in the combination treatment of various mouse tumor models such as in cholangiocarcinoma, pancreatic cancer, prostate cancer, and non-small cell lung cancer [30][31][32][33].…”

“…Also, reduction of the ATP-binding cassette-transporter genes, especially multi-drug resistance protein 3 and 4 which also resist CG-745, induce pancreatic cancer cells to sensitively respond to gemcitabine. Consequently, CG-745 leads to a synergistic anti-tumor effect on pancreatic cancer cells when combined with gemcitabine/erlotinib in mouse tumor model [32].…”

“…While HDACis in anti-cancer therapy are commonly known as apoptosis inducers through anti-cancer gene expression and cell cycle arrest, recent studies have shown anti-tumor efficacy of HDACis in certain cancer types [26][27][28][29]. CG-745 is a HDAC inhibitor, and it has been reported as a potent anti-cancer agent in cholangiocarcinoma, pancreatic cancer, prostate cancer, and non-small cell lung cancer [30][31][32][33]. In cholangiocarcinoma, CG-745 is known to target the Hippo pathway via upregulation of miR-509-3p expression [33].…”

Simvastatin functions as a heat shock protein 90 inhibitor against triple‐negative breast cancer

“…Panobinostat (LBH589), a hydroxamic acid‐based deacetylase inhibitor, is used to treat multiple myeloma. Combinations of HDACi with other agents are potential therapeutic strategies for solid tumors . Previously, we identified seven hyperacetylated lysine residues in Hsp90α after LBH589 treatment .…”

“…Combinations of HDACi with other agents are potential therapeutic strategies for solid tumors. 13,[15][16][17] Previously, we identified seven hyperacetylated lysine residues in Hsp90α after LBH589 treatment. 6 Interestingly, only acetylation at K292 increases the binding of Hsp90α to ATP.…”