Herbal diterpenoids induce growth arrest and apoptosis in colon cancer cells with increased expression of the nonsteroidal anti-inflammatory drug-activated gene.
Novel chemotherapeutic agents derived from active phytochemicals could be used as adjuvants and improve the anti-carcinogenicity of standard drug treatments. However, their precise mechanisms of action are sometimes unclear. In this study, the anti-carcinogenic effect of the herbal diterpenoid pseudolaric acid B (PAB) on the growth and apoptosis of colon cancer cells was investigated, and to compare that with the more toxic compound triptolide. PAB induced growth inhibition and apoptosis in HT-29 cells, which were associated with cell cycle arrest at the G(2)/M phase, modulation of cyclin expression and downregulation of the protooncogene c-myc. In addition, PAB also inhibited bcl-x(L) expression, induced cleavage of procaspase-3 and its substrate poly(ADP-ribose) polymerase (PARP), which together caused DNA fragmentation and nuclear chromatin condensation. Concomitantly, the modulation of the growth-related and apoptotic factors by PAB was accompanied by the increased protein and gene expression of the nonsteroidal anti-inflammatory drug-activated gene (NAG-1), which occurred along with cyclooxygenase-2 inhibition. The effects of PAB on PARP cleavage and NAG-1 overexpression were not reversible upon removal of the drug from the culture medium. Similar cytotoxic and pro-apoptotic effects were also attained by treating the HT-29 cells with another diterpenoid triptolide, but its actions on cell cycle progression and on the upstream transcriptional regulation of NAG-1 both took place in a less coherent manner. These findings exemplify the potential of herbal terpenoids, particularly PAB, in modulating colon cancer carcinogenesis through known molecular targets and precise mechanism of action.
Ko
Joshua K S
JK
Pharmacology and Toxicology Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. jksko@hkbu.edu.hk
Leung
Wan C
WC
Ho
Wai K
WK
Chiu
Pauline
P
D000972:Antineoplastic Agents, Phytogenic; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016207:Cytokines / Q000235:genetics*; D053938:DNA Fragmentation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055436:Growth Differentiation Factor 15; D019073:HT29 Cells; D006801:Humans; D015151:Immunoblotting; D007211:Indoles; D047495:PPAR gamma / Q000096:biosynthesis; D010616:Phenanthrenes / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles
D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D004224:Diterpenes; D004852:Epoxy Compounds; D005456:Fluorescent Dyes; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D007211:Indoles; D047495:PPAR gamma; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; C001899:triptolide; C007293:DAPI; C058391:pseudolaric acid B; D051546:Cyclooxygenase 2; C022616:thiazolyl blue