title: CCT327 enhances TRAIL-induced apoptosis through the induction of death receptors and downregulation of cell survival proteins in TRAIL-resistant human leukemia cells.
abstract: Tumor necrosis factor-related apoptosis‑inducing ligand (TRAIL) has potential application in cancer therapy and it has the ability to selectively kill cancer cells without affecting normal cells. However, the development of resistance to TRAIL in cancer cells cannot be avoided. This study investigated the effects of 2-(5-methylselenophen‑2‑yl)‑6,7‑methylenedioxyquinolin‑4-one (CCT327), an analogue of quinolin-4-one, on the sensitization of cancer cells to TRAIL and on TRAIL‑induced apoptosis in TRAIL‑resistance human leukemia cells (HL60‑TR). We found that CCT327 enhanced TRAIL‑induced apoptosis through upregulation of death receptors DR4 and DR5. In addition to upregulating DRs (death receptors), CCT327 suppressed the expression of decoy receptor DcR1 and DcR2. CCT327 significantly downregulated the expression of FLICE inhibitory protein (cFLIP) and other antiapoptotic proteins. We also demonstrated that CCT327 could activate p38 and JNK. Moreover, CCT327-induced induction of DR5 and DR4 was mediated by reactive oxygen species (ROS), and N-acetylcysteine (NAC) blocked the induction of DRs by CCT327. Taken together, these results showed that CCT327 combined with TRAIL treatment may provide an effective therapeutic strategy for cancer.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Yan-Jin
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Division of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan, R.O.C.
authors.forename: Ying-Chao
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Jang-Chang
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: Department of Food Science, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmaceutical Technology, College of Pharmacy and Health Care, Tajen University, Pingtung, Taiwan, R.O.C.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Tzong-Der
authors.initials: TD
authors.lastname: Way
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C000602468:CCT327; D016566:Organoselenium Compounds; D011804:Quinolines; D015363:Quinolones; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000111:Acetylcysteine