Combination Effect of Anti-Fas Antibody and Chemotherapeutic Drugs in Ovarian Cancer Cells in vitro

Wakahara, Yasunori; Nawa, Akihiro; Okamoto, Tatsuro; Hayakawa, Akihiro; Kikkawa, Fumitaka; Suganuma, Nobuhiko; Wakahara, Fumiyo; Tsutsumi, Yutaka

doi:10.1159/000227661

Cited by 28 publications

(12 citation statements)

References 14 publications

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“…Human Fas antigen consists of 325 amino acids and transduces death signal conferred by anti-Fas antibody or Fas L. Fas expression was reported in various kinds of human malignancies, including ovarian serous cystadenocarcinoma (OwenSchaub et al, 1994;Hellquist et al, 1997;Wakahara et al, 1997). In our study, 74% of patients with ovarian neoplasms showed Fas expression without significant difference in the frequency of Fas expression between histologic types.…”

Section: Discussionmentioning

confidence: 42%

Expressions of Fas ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms

et al. 2000

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Summary Expression of apoptosis-related proteins, bcl-2, Bax, Fas and Fas ligand (L), in ovarian epithelial neoplasms together with its clinical relevance was examined by immunohistochemistry. They included 36 cases with adenoma, 33 with low potential malignancy (LPM) and 63 with carcinomas. bcl-2 expression was observed in 14 of 36 cases (39%) with adenoma, five of 33 (15%) with LPM ( P < 0.05) and 12 of 63 (19%) with carcinoma ( P < 0.05). Cases with bcl-2 expression showed more favourable prognosis than those without, but the difference was not statistically significant. There was no difference in frequency of Bax and Fas expression between each histologic category. Fas L expression was observed in one of 36 cases (3%) with adenoma, but in 12 of 33 (36%) with LPM ( P < 0.001) and 42 of 63 (67%) with carcinoma ( P < 0.0001). In carcinomas, cases expressing Fas L showed a less favourable prognosis than those without ( P = 0.02). Density of CD8+ lymphocytes, possibly cytotoxic T-cells, was higher in serous carcinoma with negative Fas L expression than those with positive Fas L expression. These findings suggest that Fas L expressing carcinomas induce apoptosis in infiltrating CTL with Fas expression, and escape from immune surveillance. © 2000 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 42%

Expressions of Fas ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms

et al. 2000

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“…Similar results have been reported for FAS-mediated apoptosis in ovarian cell lines. 33,34 In contrast to TRAIL-mediated apoptosis, FAS-mediated apoptosis in ovarian cancer cells was not enhanced by 4HPR pretreatment (Figure 1d). …”

Section: Hpr Enhances Trail-mediated Toxicity In Ovarian Cancer Cellsmentioning

confidence: 92%

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

et al. 2004

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The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity. The combination of 4HPR and TRAIL enhanced cleavage of multiple caspases in the death receptor pathway (including the two initiator caspases, caspase-8 and caspase-9). The 4HPR and TRAIL combination leads to mitochondrial permeability transition, significant increase in cytochrome c release, and increased caspase-9 activation. Caspase-9 may further activate caspase-8, generating an amplification loop. Stable overexpression of Bcl-xL abrogates the interaction between 4HPR and TRAIL at the mitochondrial level by blocking cytochrome c release. As a consequence, a decrease in activation of caspase-9, caspase-8, and TRAIL-mediated apoptosis occurs. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by 4HPR is due to the increase in activation of multiple caspases involving an amplification loop via the mitochondrial-death pathway. These findings offer a promising and novel strategy for the treatment of ovarian cancer.

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“…Fas is activated by binding of Fas ligand, leading to activation of downstream death executioner factors, such as caspase-3, eventually resulting in cell death (Krammer 1999). Fas-induced apoptosis is also believed to be one of the mechanisms involved in cisplatin cytotoxity in OSE cancer cells (Uslu et al 1996, Wakahara et al 1997, a therapy often used as treatment for OSE cancer. We have examined the effect of LH on the occurrence of Fas-induced apoptosis in the human ovarian epithelial cancer cell lines HEY and Caov-3 and determined whether signaling occurs via protein kinase A (PKA) and/or protein kinase C (PKC) activation.…”

Section: Introductionmentioning

confidence: 99%

Luteinizing hormone inhibits Fas-induced apoptosis in ovarian surface epithelial cell lines

Slot¹,

Boer-Brouwer²,

Houweling³

et al. 2006

Journal of Endocrinology

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Gonadotrophins including LH have been suggested to play an important role in the etiology of epithelial ovarian cancers. The goal of the present study was to obtain more insight in the mechanism of gonadotrophin action on ovarian surface epithelium (OSE) cells. As the Fas system is known to be a major player in the regulation of the process of apoptosis in the ovary, we investigated whether LH interfered with Fas-induced apoptosis in the human OSE cancer cell lines HEY and Caov-3. Activation of Fas receptor by an agonistic anti-Fas receptor antibody induced apoptosis, as was evaluated by caspase-3 activation, poly(ADP-ribose) polymerase fragmentation, phosphatidylserine externalization and morphological changes characteristic of apoptosis. Co-treatment with LH reduced the number of apoptotic cells following activation of Fas in a transient manner, while LH by itself did not affect apoptosis or cell proliferation. The anti-apoptotic effect of LH could be mimicked by the membranepermeable cAMP analog 8-(4-chlorophenylthio)cAMP (8-CPT-cAMP), and blocked by H89, a specific inhibitor of protein kinase A (PKA). In conclusion, these findings suggest that LH protects HEY cells against Fas-induced apoptosis through a signaling cascade involving PKA. Although it is plausible that in vivo LH might also enhance OSE tumor growth through inhibition of apoptosis, further research is necessary to confirm this hypothesis.

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Combination Effect of Anti-Fas Antibody and Chemotherapeutic Drugs in Ovarian Cancer Cells in vitro

Cited by 28 publications

References 14 publications

Expressions of Fas ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms

Expressions of Fas ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

Luteinizing hormone inhibits Fas-induced apoptosis in ovarian surface epithelial cell lines

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