A redox-silent analogue of tocotrienol acts as a potential cytotoxic agent against human mesothelioma cells.
OBJECTIVE
Malignant mesothelioma is an aggressive cancer with no effective treatment options. A redox-silent analogue of alpha-tocotrienol, 6-O-carboxypropyl-alpha-tocotrienol (T3E) is a new potential anti-carcinogenic agent with less toxic effect on non-tumorigenic cells. Here, we evaluated the effect of T3E on killing of chemoresistant mesothelioma cell (H28).


METHODS
The cytotoxic effect of T3E was evaluated by a WST-1 assay, and cell cycle and apoptosis analysis were done by FACS. Each signal molecule's activity was determined by protein array and immunoblot analysis.


RESULTS
T3E effectively inhibited H28 cell growth at practical pharmacological concentrations (10-20 muM) without any effect on non-tumorigenic mesothelial cell (Met-5A). Inhibition of H28 cell growth by T3E mediated through G2/M arrest in cell cycle and induction of apoptosis. Protein array and immunoblot analyses revealed that T3E inhibited the activation of epidermal growth factor receptor (EGFR) via the inactivation of the Src family of protein tyrosine kinases (Src). However, the blockade of the EGFR signaling was not associated with the T3E-dependent H28 cell growth control. In addition to Src inactivation, T3E inhibited signal transduction and activation of transcription Stat3. A combination of an Src inhibitor, PP2, and a Stat3 inhibitor, AG490, induced G2/M arrest and enhanced apoptosis compared with PP2 alone. These results suggest that T3E suppresses H28 cell growth via the inhibition of Src activation and Src-independent Stat3 activation.


CONCLUSIONS
T3E can be a new effective therapeutic agent against chemoresistant mesothelioma cells.
Kashiwagi
Korehito
K
Project for Complementary Factors, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo, Japan.
Virgona
Nantiga
N
Harada
Kayono
K
Kido
Wakiko
W
Yano
Yoshihisa
Y
Ando
Akira
A
Hagiwara
Kiyokazu
K
Yano
Tomohiro
T
D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D010084:Oxidation-Reduction; D040081:Protein Array Analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D024508:Tocotrienols / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D019061:src-Family Kinases / Q000378:metabolism
C501588:6-O-carboxypropyl-alpha-tocotrienol; D000970:Antineoplastic Agents; D000975:Antioxidants; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D024508:Tocotrienols; D019061:src-Family Kinases