Wenfang Bao1, Zhe Zhu2, Yong Gao3, Jingde Chen4,5. 1. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, 150 Ji-Mo Rd, Shanghai, 200120, China. 2. Department of Colorectal Surgery, Department of General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. 3. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, 150 Ji-Mo Rd, Shanghai, 200120, China. drgaoyong@tongji.edu.cn. 4. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, 150 Ji-Mo Rd, Shanghai, 200120, China. 1600092@tongji.edu.cn. 5. Department of Oncology, Ji'an Hospital, Shanghai East Hospital, Ji'an, 343000, China. 1600092@tongji.edu.cn.
Abstract
BACKGROUND: Gastric cancer (GC) remains a significant health problem and carries with it substantial morbidity and mortality. Chidamide is a novel and orally administered histone deacetylase (HDAC) inhibitor and has been demonstrated its anti-tumor efficacy on different kinds of hematological and solid tumors. However, the underlying mechanism of chidamide resistance is still poorly characterized. METHODS: We established chidamide resistant GC cell lines, AGS ChiR and MGC803 ChiR and investigated the toxicologic effects through cell survival, colony formation and flow cytometry assays in vitro, and a subcutaneous xenograft model in vivo. RNA-sequence was then performed to screen chidamide resistance-associated genes between AGS and AGS ChiR cells. The role of Lymphocyte cytosolic protein 1 (LCP1) in chidamide resistance was explored by gain- and loss-of-function analyses. RESULTS: We found that chidamide significantly inhibited cell proliferation and induced the apoptosis in a concentration-dependent manner in wild-type GC cell lines as compared to chidamide resistant cell lines. The transcriptomic profiling, quantitative RT-PCR, and western blot data revealed that LCP1 was upregulated in AGS ChiR cells compared with parental cells. Overexpression of LCP1 conferred and knockdown of LCP1 attenuated the chidamide resistance of GC cells. Epigenetic derepression of LCP1 by chidamide may be a possible reason for the contribution of LCP1 to chidamide resistance. CONCLUSIONS: These findings illustrated that LCP1 may play a chidamide resistance role in GC, suggesting that LCP1 could be a potential target for the therapy of GC combined with chidamide.
BACKGROUND: Gastric cancer (GC) remains a significant health problem and carries with it substantial morbidity and mortality. Chidamide is a novel and orally administered histone deacetylase (HDAC) inhibitor and has been demonstrated its anti-tumor efficacy on different kinds of hematological and solid tumors. However, the underlying mechanism of chidamide resistance is still poorly characterized. METHODS: We established chidamide resistant GC cell lines, AGS ChiR and MGC803 ChiR and investigated the toxicologic effects through cell survival, colony formation and flow cytometry assays in vitro, and a subcutaneous xenograft model in vivo. RNA-sequence was then performed to screen chidamide resistance-associated genes between AGS and AGS ChiR cells. The role of Lymphocyte cytosolic protein 1 (LCP1) in chidamide resistance was explored by gain- and loss-of-function analyses. RESULTS: We found that chidamide significantly inhibited cell proliferation and induced the apoptosis in a concentration-dependent manner in wild-type GC cell lines as compared to chidamide resistant cell lines. The transcriptomic profiling, quantitative RT-PCR, and western blot data revealed that LCP1 was upregulated in AGS ChiR cells compared with parental cells. Overexpression of LCP1 conferred and knockdown of LCP1 attenuated the chidamide resistance of GC cells. Epigenetic derepression of LCP1 by chidamide may be a possible reason for the contribution of LCP1 to chidamide resistance. CONCLUSIONS: These findings illustrated that LCP1 may play a chidamide resistance role in GC, suggesting that LCP1 could be a potential target for the therapy of GC combined with chidamide.
Authors: Zhi-Qiang Ning; Zhi-Bin Li; Michael J Newman; Song Shan; Xin-Hao Wang; De-Si Pan; Jin Zhang; Mei Dong; Xin Du; Xian-Ping Lu Journal: Cancer Chemother Pharmacol Date: 2011-11-12 Impact factor: 3.333
Authors: Jesús F San-Miguel; Vânia T M Hungria; Sung-Soo Yoon; Meral Beksac; Meletios Athanasios Dimopoulos; Ashraf Elghandour; Wieslaw Wiktor Jedrzejczak; Andreas Günther; Thanyaphong Na Nakorn; Noppadol Siritanaratkul; Paolo Corradini; Suporn Chuncharunee; Je-Jung Lee; Robert L Schlossman; Tatiana Shelekhova; Kwee Yong; Daryl Tan; Tontanai Numbenjapon; Jamie D Cavenagh; Jian Hou; Richard LeBlanc; Hareth Nahi; Lugui Qiu; Hans Salwender; Stefano Pulini; Philippe Moreau; Krzysztof Warzocha; Darrell White; Joan Bladé; WenMing Chen; Javier de la Rubia; Peter Gimsing; Sagar Lonial; Jonathan L Kaufman; Enrique M Ocio; Ljupco Veskovski; Sang Kyun Sohn; Ming-Chung Wang; Jae Hoon Lee; Hermann Einsele; Monika Sopala; Claudia Corrado; Bourras-Rezki Bengoudifa; Florence Binlich; Paul G Richardson Journal: Lancet Oncol Date: 2014-09-18 Impact factor: 41.316