ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation

Peng, Ueihuei; Wang, Wenwen; Pei, Sa; Ou, Yunchao; Hu, Pengchao; Liu, Wanhong; Song, Jiquan

doi:10.3892/or.2016.5340

Cited by 27 publications

(31 citation statements)

References 40 publications

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“…Epigenetic mechanisms may be targeted by inhibiting key transcription factors, such as WNT5 or STAT3 [ 134 , 135 , 222 , 240 ], or by the use of microRNA mimetics [ 59 ] or HDAC inhibitors [ 111 , 163 , 241 , 242 , 243 , 244 , 245 ]. HDAC inhibitors have also been investigated in combination with a CDK inhibitor with promising in vitro and in vivo activity [ 233 , 244 , 246 ].…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Proietti

Skroza

Bernardini

et al. 2020

Cancers

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This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Proietti

Skroza

Bernardini

et al. 2020

Cancers

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“…is proven to have antitumor effects in various cancers in monotherapy or in combination with other agents (9)(10)(11)(12)(13)(14)(15)(16). Besides ACY-1215, which has been explored widely for its clinical efficacy, other novel HDAC6-selective inhibitors, ACY-241 and A452, need further extensive research.…”

Section: Discussionmentioning

confidence: 99%

HDAC6-selective inhibitors enhance anticancer effects of paclitaxel in ovarian cancer cells

et al. 2021

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Histone deacetylase 6 (HDAC6)-selective inhibitors are potent anticancer agents that are gaining increasing attention and undergoing various developments. These have been approved or are under clinical trials for use with other anticancer agents, such as pomalidomide, anti-programmed death-ligand 1 antibody and paclitaxel, for various types of cancer, including solid tumors. In the present study, a second generation HDAC6-selective inhibitor, ACY-241 (citarinostat), and a novel inhibitor, A452, exhibited synergistic anticancer effects with paclitaxel in AT-rich interaction domain 1A-mutated ovarian cancer in vitro. Co-treatment of paclitaxel and the two HDAC6 inhibitors synergistically decreased cell growth and viability of TOV-21G. Furthermore, the protein expression levels of pro-apoptotic markers, such as poly(ADP-ribose) polymerase, cleaved caspase-3, Bak and Bax, were increased, whereas the expression levels of anti-apoptotic markers, such as Bcl-xL and Bcl-2, were decreased synergistically. Treatment with all drug combinations increased the portion of apoptotic cells in fluorescence-activated cell sorting analysis. These results demonstrated synergy between paclitaxel and HDAC6-selective inhibitors, providing further impetus for clinical trials of combination therapy using HDAC6-selective inhibitors, not only in ovarian cancer but also in other tumors.

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“…In glioblastoma, tumor cell growth is significantly inhibited by ACY-1215 through transforming growth factor β receptor signaling, which induces SMAD2 phosphorylation and increased P21 expression 13 . In BRAF-mutant melanoma cells, ACY-1215 sensitizes vemurafenib-induced cell proliferation inhibition and apoptosis through induction of ER stress and inactivation of ERK 14 .…”

Section: Discussionmentioning

confidence: 99%

Ricolinostat (ACY-1215) suppresses proliferation and promotes apoptosis in esophageal squamous cell carcinoma via miR-30d/PI3K/AKT/mTOR and ERK pathways

Cao

Wang

et al. 2018

Cell Death Dis

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Ricolinostat (ACY-1215), a first-in-class selective HDAC6 inhibitor, exhibits antitumor effects alone or in combination with other drugs in various cancers. However, its efficacy in esophageal cancer remains unclear. In this study, we found that the high expression of HDAC6 was associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) tissues. Then, we identified that ACY-1215 significantly inhibited cellular proliferation in ESCC, and caused G2/M phase arrest and apoptosis. We further demonstrated that ACY-1215 treatment reduced the expression of PI3K, P-AKT, P-mTOR, and P-ERK1/2 and increased that of Ac-H3K9 and Ac-H4K8. In addition, using miRNA microarray and bioinformatics analysis, we detected that ACY-1215 promoted miR-30d expression, and PI3K regulatory subunit 2 (PIK3R2) was a direct target of miR-30d. Anti-miR-30d partially rescued the G2/M phase arrest and apoptosis caused by ACY-1215 treatment. The reductions in PI3K, P-AKT, and P-mTOR expression were also partially reversed by miR-30d inhibitor. Furthermore, the effects of ACY-1215 inhibited ESCC proliferation were validated in a mouse xenograft model in vivo. In conclusion, our study showed that ACY-1215 suppressed proliferation and promoted apoptosis in ESCC via miR-30d/PI3K/AKT/mTOR and ERK pathways and that ACY-1215 may be a promising antitumor agent in ESCC.

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ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation

Cited by 27 publications

References 40 publications

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

HDAC6-selective inhibitors enhance anticancer effects of paclitaxel in ovarian cancer cells

Ricolinostat (ACY-1215) suppresses proliferation and promotes apoptosis in esophageal squamous cell carcinoma via miR-30d/PI3K/AKT/mTOR and ERK pathways

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