NF-κB signaling inhibition and anticancer activities of LLDT-246 on human colorectal cancer HCT-116 cells in vitro

Meng Li; Xiu'e Wang; Ming Liu; Xin Qi; Jing Li

doi:10.1016/j.biopha.2014.05.002

NF-κB signaling inhibition and anticancer activities of LLDT-246 on human colorectal cancer HCT-116 cells in vitro

Biomed Pharmacother. 2014 Jun;68(5):527-35. doi: 10.1016/j.biopha.2014.05.002. Epub 2014 Jun 10.

Authors

Meng Li¹, Xiu'e Wang¹, Ming Liu¹, Xin Qi², Jing Li³

Affiliations

¹ Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China.
² Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China. Electronic address: [email protected].
³ Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China. Electronic address: [email protected].

PMID: 24986326
DOI: 10.1016/j.biopha.2014.05.002

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.

Keywords: Derivative; NF-κB; Tripotolide; Tripterygium wilfordii Hook F.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Apoptosis / genetics
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Cell Survival / drug effects
Cell Survival / genetics
Colorectal Neoplasms / enzymology
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
Diterpenes / chemistry
Diterpenes / pharmacology*
Down-Regulation / drug effects
Down-Regulation / genetics
Drug Synergism
Epoxy Compounds / chemistry
Epoxy Compounds / pharmacology
Gene Expression Regulation, Neoplastic / drug effects
HCT116 Cells
Humans
I-kappa B Proteins / metabolism
Inhibitory Concentration 50
Mice
Mitochondria / drug effects
Mitochondria / metabolism
NF-KappaB Inhibitor alpha
NF-kappa B / metabolism*
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Phenanthrenes / chemistry
Phenanthrenes / pharmacology*
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects*
Signal Transduction / genetics
Transcription Factor RelA / metabolism
Tumor Necrosis Factor-alpha / pharmacology
Tumor Suppressor Protein p53 / metabolism
Up-Regulation / drug effects
Up-Regulation / genetics

Substances

Antineoplastic Agents
Diterpenes
Epoxy Compounds
I-kappa B Proteins
LLDT-246
NF-kappa B
NFKBIA protein, human
Neoplasm Proteins
Nfkbia protein, mouse
Phenanthrenes
STAT3 Transcription Factor
Transcription Factor RelA
Tumor Necrosis Factor-alpha
Tumor Suppressor Protein p53
NF-KappaB Inhibitor alpha
triptolide
Proto-Oncogene Proteins c-akt