Enhanced susceptibility to apoptosis of oral squamous cell carcinoma cells subjected to combined treatment with anticancer drugs and phosphatidylinositol 3-kinase inhibitors.
The purpose of this study was to determine whether phosphatidylinositol 3-kinase (PI 3-K) inhibitors could modulate the apoptotic activity of the anticancer drugs cisplatin, 5-fluorouracil or docetaxel in an oral squamous cell carcinoma (OSCC) cell line, HSC-2. In preliminary experiments, cisplatin, 5-fluorouracil and docetaxel inhibited the proliferation of OSCC cells in a dose-dependent manner. We found that two PI 3-K inhibitors, wortmannin and LY294002, markedly suppressed the phosphorylation of Akt in OSCC cells. Treatment of OSCC cells with PI 3-K inhibitors significantly enhanced cisplatin-, 5-fluorouracil- or docetaxel-induced apoptosis. Caspase-3 and -9 inhibitors, but not a caspase-8 inhibitor, reduced anticancer drug-mediated apoptosis in PI 3-K inhibitor-treated OSCC cells, suggesting that the apoptotic pathway induced by the combination of anticancer drug therapy and PI 3-K inhibition may be functionally related to the intrinsic apoptotic pathway in OSCC cells. Expression of Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1), and X-linked IAP was down-regulated, and expression of Bax was up-regulated by PI 3-K inhibitors, while that of Bcl-xL, Bak and cIAP-2 was not attenuated. We also found that Bad phosphorylation was down-regulated by PI 3-K inhibitors. These results suggested that inhibition of PI 3-K enhances the susceptibility of OSCC cells to anticancer drug-mediated apoptosis through regulation of expression and post-translational modification of both pro- and anti-apoptotic proteins. These findings could potentially lead to new strategies for improving the efficacy of anticancer drugs in OSCC cells.
Iwase
Masayasu
M
Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Ota-ku, Tokyo 145-8515, Japan. iwase@senzoku.showa-u.ac.jp
Yoshiba
Sayaka
S
Uchid
Makiko
M
Takaoka
Sayaka
S
Kurihara
Yuji
Y
Ito
Daisuke
D
Hatori
Masashi
M
Shintani
Satoru
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C494819:BAD protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051025:bcl-Associated Death Protein; D051057:Proto-Oncogene Proteins c-akt