title: NF-κB signaling inhibition and anticancer activities of LLDT-246 on human colorectal cancer HCT-116 cells in vitro.
abstract: Triptolide attracts attention for its anti-inflammatory, immune modulation, anti-proliferative and pro-apoptotic activity, but the clinical application of triptolide is restricted by its serious toxicity. Here, we demonstrate LLDT-246, a new triptolide derivative, exhibited a little more potent activity of NF-κB inhibition and cytotoxicity whether acting alone or in combination with TNF-α on colorectal cancer HCT-116 cells than its maternal compound, and showed low toxic to non-cancer cells. Mechanism study revealed that LLDT-246 inhibited phosphorylation of AKT, p-GSK3β and p-mTOR, however, no significant effects were found on the level of p-ERK and p-JNK, along with HSP70, indicating LLDT-246 indirectly affects NF-κB and suppresses NF-κB signaling largely by interpreting AKT/GSK3β/mTOR pathway. Altogether, LLDT-246 is a promising anticancer derivative of triptolide, further studies in vivo and about detailed mechanism of LLDT-246 is required in the future.
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China.
authors.forename: Xiu'e
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China. Electronic address: qxhin@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China. Electronic address: ljlilac@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D020672:I-kappa B Proteins; C000596365:LLDT-246; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; C000606205:Nfkbia protein, mouse; D010616:Phenanthrenes; D050796:STAT3 Transcription Factor; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D000072000:NF-KappaB Inhibitor alpha; C001899:triptolide; D051057:Proto-Oncogene Proteins c-akt
keywords: Derivative; NF-κB; Tripotolide; Tripterygium wilfordii Hook F