Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells.
To date, the most effective cure for metastatic melanoma remains the surgical resection of the primary tumor. Recently, tocotrienol-rich-fraction has shown antiproliferative effect on cancer cells. To elucidate this anticancer property in malignant melanoma, this study aimed, first, to identify the most potent isomer for eliminating melanoma cells and second to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of procaspases and the accumulation of sub-G1 cell population. Examination of the prosurvival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R, and Id family proteins. Meanwhile, gamma-tocotrienol treatment also resulted in induction of JNK signaling pathway, and inhibition of JNK activity by selective inhibitor was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, synergistic effect was observed when cells were cotreated with gamma-tocotrienol and chemotherapy drugs. Together, our results demonstrated for the first time the anti-invasion and chemonsensitization effect of gamma-tocotrienol against human malignant melanoma cells.
Chang
Piek Ngoh
PN
Davos Life Science Pte. Ltd., Cancer Research Laboratory, 138667, Singapore.
Yap
Wei Ney
WN
Lee
Davy Tak Wing
DT
Ling
M T
MT
Wong
Y C
YC
Yap
Yee Leng
YL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015820:Cadherins / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D003606:Dacarbazine / Q000494:pharmacology; D000077143:Docetaxel; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D015820:Cadherins; D002839:Chromans; D043823:Taxoids; D014810:Vitamin E; D000077143:Docetaxel; C013649:plastochromanol 8; D003606:Dacarbazine; D048031:JNK Mitogen-Activated Protein Kinases