Non-steroidal anti-inflammatory drugs induce apoptosis in gastric cancer cells through up-regulation of bax and bak

Aspirin- and non-steroidal anti-inflammatory drug (NSAID)-induced apoptosis is one of the important mechanisms for their anti-tumour effect in gastric cancer. We aimed at determining the role of bcl-2 family proteins and caspases in the apoptotic process. Gastric cancer cell lines AGS (wild-type p53) and MKN-28 (mutant p53) were used. Cell proliferation was measured by MTT assay. Apoptosis was determined by acridine orange staining. Protein expressions were determined by western blotting. Aspirin and indomethacin inhibited cell proliferation and induced apoptosis in both cells. AGS cells were more sensitive compared with MKN-28 cells. The pro-apoptotic proteins bax and bak were overexpressed after treatment, while the protein level of bcl-2 remained unchanged. Apoptosis was accompanied by an increase in caspase-3 activity and cleavage of caspase-3 and poly(ADP-ribose) polymerase. Inhibition of caspase-3 rescued aspirin-induced apoptosis. Our results suggest that one of the major pathways which mediates the anti-tumour response of aspirin and indomethacin in gastric cancer cells is through up-regulation of bax and bak and activation of caspase-3. Bax and bak are important in the chemoprevention of gastric cancer.     

UBE2C对宫颈癌HeLa细胞增殖、迁移及侵袭能力的影响

目的:研究泛素结合酶E2C（ubiquitin-conjugating enzyme E2C,UBE2C）在宫颈癌细胞中的表达情况,并明确UBE2C对宫颈癌HeLa细胞增殖、迁移及侵袭能力的影响。方法:首先查阅GEPIA数据库,了解UBE2C在宫颈癌中的表达;其次通过qRT-PCR和Western blotting 法明确UBE2C在宫颈癌HeLa细胞及正常宫颈上皮细胞End1/E6E7中表达差异,然后分别构建si-UBE2C及si-NC转染宫颈癌HeLa细胞,检测转染后细胞中 UBE2C mRNA和蛋白表达;最后采用CCK-8 实验、细胞划痕实验及Transwell实验检测转染后细胞的增殖、迁移和侵袭能力的变化,并鉴定UBE2C下游靶基因PTEN、P-p53的表达情况。结果:UBE2C在宫颈癌中高表达,能够促进宫颈癌细胞的增殖、迁移及侵袭能力,并下调抑癌基因PTEN、P-p53的表达。结论:UBE2C能够加重宫颈癌细胞恶性表型;UBE2C可能作为宫颈癌诊断及治疗的判定指标之一。     

Flavopiridol potentiates the cytotoxic effects of radiation in radioresistant tumor cells in which p53 is mutated or Bcl-2 is overexpressed

PURPOSE: Loss of the cell-cycle regulatory protein p53 or overexpression of the antiapoptotic protein Bcl-2 is associated with resistance to radiation in several types of cancer cells. Flavopiridol, a synthetic flavone, inhibits the growth of malignant tumors cells in vitro and in vivo through multiple mechanisms. The purpose of the present study is to clarify whether flavopiridol enhances the cytotoxic effects of radiation in tumor cells that contain dysfunction p53 or that overexpress Bcl-2. METHODS AND MATERIALS: A human glioma cell line (A172/mp53) stably transfected with a plasmid containing mutated p53 and a human cervical cancer cell line (HeLa/bcl-2) transfected with a bcl-2 expression plasmid were used. Cells were incubated with flavopiridol for 24 h after radiation, and then cell viability was determined by a colony formation assay. Foci of phosphorylated histone H2AX were also evaluated as a sensitive indicator of DNA double-strand breaks. RESULTS: Compared with the parental wild-type cells, both transfected cell lines were more resistant to radiation. Post-treatment with flavopiridol increased the cytotoxic effects of radiation in both transfected cell lines, but not in their parental wild-type cell lines. Post-treatment with flavopiridol inhibited sublethal damage repair as well as the repair of DNA double-strand breaks in response to radiation. CONCLUSIONS: Flavopiridol enhanced the cytotoxic effect of radiation in radioresistant tumor cells that harbor p53 dysfunction or Bcl-2 overexpression. A combination treatment of flavopiridol with radiation has the potential to conquer the radioresistance of malignant tumors induced by the genetic alteration of p53 or bcl-2.     

Inotodiol Inhabits Proliferation and Induces Apoptosis through Modulating Expression of cyclinE,p27, bcl-2, and bax in Human Cervical Cancer HeLa Cells

Inonotus obliquus is a medicinal mushroom that has been used as an effective agent to treat various diseasessuch as diabetes, tuberculosis and cancer. Inotodiol, an included triterpenoid shows significant anti-tumor effect.However, the mechanisms have not been well documented. In this study, we aimed to explore the effect of inotodiolon proliferation and apoptosis in human cervical cancer HeLa cells and investigated the underlying molecularmechanisms. HeLa cells were treated with different concentrations of inotodiol. The MTT assay was used toevaluate cell proliferating ability, flow cytometry (FCM) was employed for cell cycle analysis and cell apoptosis,while expression of cyclinE, p27, bcl-2 and bax was detected by immunocytochemistry. Proliferation of HeLacells was inhibited by inotodiolin a dose-dependent manner at 24h (r=0.9999, p<0.01). A sub-G1 peak (apoptoticcells) of HeLa cells was detected after treatment and the apoptosis rate with the concentration and longerincubation time (r=1.0, p<0.01), while the percentage of cells in S phase and G2/M phase decreased significantly.Immunocytochemistry assay showed that the expression of cyclin E and bcl-2 in the treated cells significantlydecreased, while the expression of p27 and bax obviously increased, compared with the control group (p<0.05).The results of our research indicate that inotodiol isolated from Inonotus obliquus inhibited the proliferationof HeLa cells and induced apoptosis in vitro. The mechanisms may be related to promoting apoptosis throughincreasing the expression of bax and cutting bcl-2 and affecting the cell cycle by down-regulation the expressionof cyclin E and up-regulation of p27. The results further indicate the potential value of inotodiol for treatmentof human cervical cancer.     

基于槲皮素标记的金属有机框架放疗联合阿霉素诱导宫颈癌HeLa细胞凋亡的研究

目的 探讨基于槲皮素(Quercetin,QU;3,3′,4′,5,7-五羟基黄酮)标记的金属有机框架(Zr metal organic frameworks,Zr-MOF)放疗(Radiation therapy,RT)联合阿霉素(Doxorubicin,DOX)对宫颈癌HeLa细胞增殖和凋亡的影响。方法 将宫颈癌HeLa细胞分为对照组、RT组、阿霉素处理组(Zr-MOF-DOX+RT)、QU处理组(Zr-MOF-QU+RT)及联合处理组(Zr-MOF-QU-DOX+RT);采用细胞克隆形成法检测各处理组HeLa细胞的增殖活性;蛋白印迹法及免疫荧光法检测各组细胞凋亡蛋白Caspase-3及缺氧诱导因子1α(Hypoxia inducible factor-1α,HIF-1α)的表达水平。结果 联合处理组细胞的增殖能力明显低于其他各组,差异具有统计学意义(P＜0.05);联合处理组HIF-1α蛋白表达量明显低于其他各组(P＜0.05),联合处理组Caspase-3蛋白的表达含量明显高于其他各组(P＜0.05)。结论 基于槲皮素标记的金属有机框架放疗联合阿霉素对HeLa细胞的抑制作用更显著,联合处理组通过上调凋亡蛋白Caspase-3及下调HIF-1α蛋白表达进而产生更强的抗肿瘤作用。     

白桦脂酸对HeLa细胞的抑制作用及其机制研究

背景与目的:白桦脂酸(betulinic acid)是一类白桦树皮中提取的天然五环三萜类化合物,具有广泛的药理活性,有研究表明白桦脂酸能诱导多种肿瘤细胞凋亡,但其对人宫颈癌细胞的作用尚缺乏文献资料。本研究旨在探讨白桦脂酸体外对人宫颈癌HeLa细胞的增殖抑制作用及其机制。方法:采用四甲基偶氮唑盐(MTT)法测定白桦脂酸对HeLa细胞生长的抑制作用;Hoechst33258荧光染色检测白桦脂酸处理HeLa细胞后发生凋亡的形态变化;采用流式细胞术(flow cetemotry,FCM)检测白桦脂酸处理HeLa细胞后诱导凋亡作用及凋亡率;采用蛋白质印迹法(Western blot)检测caspase-3、细胞色素C(Cyto C)等凋亡相关蛋白的表达。结果:MTT分析表明,白桦脂酸抑制HeLa细胞增殖,并呈时间和剂量依赖性(P<0.01),其24、48和72 h的半数抑制浓度(50%inhibiting concentration,IC50)分别为20.36、15.45和12.02μg/mL;白桦脂酸处理HeLa细胞后,Hoechst33258染色出现典型的凋亡特征,且流式细胞术检测Annexin-Ⅴ/PI双染出现早期凋亡细胞;Westernblot检测结果显示经白桦脂酸处理后HeLa细胞的caspase-3、Cyto C蛋白表达均上调。结论:白桦脂酸可显著抑制人宫颈癌HeLa细胞的增殖,并可能通过上调caspase-3、Cyto C蛋白的表达诱导人宫颈癌HeLa细胞凋亡。     

Apoptosis-mediated inhibition of human breast cancer cell proliferation by lemon citrus extract

Dietary phytochemicals have a variety of antitumor properties. In the present study, the antitumor activity of methanolic extract of lemon fruit (lemon extract; LE) (LE) on the MCF-7 breast cancer cell line was investigated in vitro. Apoptotic cell death was analyzed using the TUNEL assay. In addition, the apoptosis mediated by LE extract in the MCF-7 cells was associated with the increased expression of the tumor suppressor p53 and caspase-3. Additionally, the expression of a pro-apoptotic gene, bax, was increased, and the expression of an anti-apoptotic gene, bcl-2, was decreased by LE extract treatment, resulting in a shift in the Bax:Bcl-2 ratio to one that favored apoptosis. The expression of a major apoptotic gene, caspase-3, was increased by LE extract treatment. In light of the above results, we concluded that LE extract can induce the apoptosis of MCF-7 breast cancer cells via Bax-related caspase-3 activation. This study provides experimental data that are relevant to the possible future clinical use of LE to treat breast cancer.     

组蛋白去乙酰化酶抑制剂SAHA与紫杉醇联用诱导宫颈癌HeLa细胞凋亡的实验

目的 探讨组蛋白乙酰化抑制剂SAHA联合紫杉醇体外对宫颈癌HeLa细胞增殖抑制效果及其机制。方法 分别设置空白对照组SAHA（10 μmol/L）组、紫杉醇（10 nmol/L）组、SAHA（10 μmol/L）+紫杉醇（10 nmol/L）联合组,采用MTT法检测各组HeLa细胞的抑制率,采用流式细胞术检测HeLa细胞凋亡情况和细胞周期。结果 MTT结果显示经SAHA组、紫杉醇组和联合组分别处理24、48 h后,与SAHA和紫杉醇组比较,联合组能够显著抑制HeLa细胞的增殖,差异有统计学意义,且二者具有叠加作用（Q=0.861, Q=1.25）; HeLa细胞的凋亡实验结果显示联合组的凋亡率分别高于紫杉醇组、SAHA组;HeLa细胞周期实验发现：联合组处理后的HeLa细胞主要处于G0/G1期,提示SAHA与紫杉醇联合使用能够抑制HeLa细胞有丝分裂过程中的DNA合成和复制。结论 SAHA与紫衫醇联用能够抑制宫颈癌HeLa细胞增殖,增强诱导HeLa细胞凋亡的能力,阻滞细胞周期,最终增强抗肿瘤的能力。     

Enhanced apoptosis and radiosensitization by combined 13-cis-retinoic acid and interferon-alpha2a; role of RAR-beta gene.

PURPOSE: Combined use of 13-cis-retinoic acid (cRA) and interferon-alpha2a (IFNalpha) induced significant radiosensitization in human cervical cancer ME-180 cell line, whereas it failed to achieve similar radiation enhancement in HeLa cells. The differential radiosensitization could be from the difference of retinoic acid receptor (RAR) expression because RAR-beta was highly expressed in ME-180 cells in contrast to the HeLa cells where RAR-beta was not detectable. We examined the role of this gene in mediating radiosensitization by cRA and IFNalpha, and explored the mechanism of radiation-induced cell killing. METHODS AND MATERIALS: Human cervical cancer cell lines, ME-180 and HeLa, were treated with cRA and IFNalpha followed by radiation. Apoptosis and radiosensitization were quantitated by TUNEL assay (in situ DNA nick end labeling) and colony-forming ability of surviving cells. The cells were transfected with bcl-2 gene and RAR-beta gene to test the role of these genes in mediating radiosensitization and apoptosis. RESULTS: Synergistic radiosensitization and apoptosis was observed by combined use of cRA and IFNalpha with radiation in ME-180 cells which express high level of RAR-beta mRNA, whereas these were not seen in HeLa cells where RAR-beta mRNA is not detectable. Both radiosensitization and apoptosis were abolished by bcl-2 gene in ME-180 cells. RAR-beta gene transfection induced similar radiation enhancement and apoptosis in HeLa cells. CONCLUSION: Apoptosis and radiation response were enhanced in the cells with high level of RAR-beta mRNA expression. The RAR-beta gene appears to mediate the radiation-induced apoptosis by cRA and IFNalpha. These findings indicate that presence of RAR-beta in the cancer cells could be exploited for patient selection in using these drugs for apoptosis and radiosensitization.     

EFFECTS OF CURCUMIN ON PROLIFERATION AND APOPTOSIS OF HUMAN CERVICAL CARCINOMA HeLa CELLS IN VITRO

Curcumin,adeferuloymethane,isamajoractivecomponentofthefoodflavorturmetric(CurcumalLonga).Becauseofitsstablecolourandlusterandlowtoxicity,curcuminhasbeenwidelyusedasfoodadditiveandstain.Recently,ithasbeenreportedtopossesantiinflammatory,antioxidationandantiviralactivities.Now,attentionhasbeenfocusedonitsantitumoractivity[1].InvitrocurcuminwasfoundtoinduceapoptosisofawidevarietyoftumorcellsincludingmicesarcomaS180cells,humancoloncarcinomaHT-29cells,humanrenalcarcinoma293cells,humanlivercarcin…     

Chemoradiation of cervical cancer cells: targeting human papillomavirus E6 and p53 leads to either augmented or attenuated apoptosis depending on the platinum carrier ligand

Recent clinical trials comparing concurrent chemotherapy and radiation with radiation alone in cervical cancer have shown that chemoradiation reduces the risk of death by 30-50%. Despite the clinical success, treatment responses at the cellular level are still inadequately explored. A key event in cervical carcinogenesis is the disruption of p53 tumor suppressor pathway by human papillomavirus (HPV) E6 oncogene. We found that regardless of the HPV type in SiHa (HPV 16+) CaSki (HPV 16+), HeLa (HPV 18+), and UT-DEC-1 (HPV 33+) cell lines, cisplatin, carboplatin, and a novel platinum compound, oxaliplatin, activated a p53 reporter and reduced the HPV E6 mRNA. Carboplatin and oxaliplatin treatment led also to stabilization of p53, whereas none of the platinums changed p73 levels. After irradiation (IR) alone, a decrease in HPV E6 mRNA levels and an activation of the p53-reporter were detected in SiHa, CaSki, and HeLa cells, but not in UT-DEC-1 cells. Concomitant platinum treatment and IR led to poly(ADP-ribose) polymerase cleavage as a sign of caspase-3 activation and apoptosis. Clonogenic survival was enhanced by expressing a dominant negative p53 or ectopic HPV16 E6 in SiHa and HeLa cells treated with IR, carboplatin, or oxaliplatin or with a combination of IR + carboplatin or oxaliplatin. In contrast, dominant negative p53 or ectopic HPV 16 E6 sensitized the cells to cisplatin. Pt chemotherapeutics and radiation had a synergistic cytotoxic effect as determined by Bliss independence criterion. Taken together, p53 has a significant role in the cellular response to chemoradiation treatment in cervical cancer cell lines, but p53 activity may have a dramatically different effect on cell survival depending on the platinum carrier ligand.     

Curcumin Analogue A501 induces G2/M Arrest and Apoptosis in Non-small Cell Lung Cancer Cells

Curcumin and its analogues have been reported to exert anti-cancer activity against a variety of tumors. Here, we reported A501, a new curcumin analogue. The effect of A501 on cell viability was detected by MTT assay, the result showed that A501 had a better inhibiting effect on the four non-small cell lung cancer (NSCLC) cells than that of curcumin. Moreover, Colony forming experiment showed A501 significant restrained cell proliferation. Flow cytometry displayed A501 can cause G2/M arrest and induce apoptosis. Western blotting showed thatA501 decreased the expression of cyclinB1, cdc-2, bcl-2, while increased the expression of p53, cleaved caspase-3 and bax. In conclusion, curcumin analogues A501 played antitumor activity by inhibiting cell proliferation andinducing apoptosis of NSCLC cells. And it was likely to be a promising starting point for the development of curcumin-based anticancer drugs.     

Plasmid vaccine encoding HN gene from newcastle disease virus has marked antitumoral effect in vitro

Objective: To explore the antitumor effects of hemaagglutinin-neuraminase gene (HN gene) from Newcastle disease virus. Methods: Plasmid vaccine of pIRHN was constructed and transfected into HeLa cells.The expression of HN was analyzed by Western blot analysis, and the mode of cell death was detected by fluorescence microscope, gel electrophoresis and TUNEL assay and the expression of p53 and bcl-2 was also analyzed in transfected Hela cells. The effect of pIRHN on sialic acid contents in the Hela cell was examined. Results: plRHN nucleic acid vaccines could be expressed in eukaryotic cell. pIRHN could induce apoptosis after HeLa cells were transfected. The effect of antitumor responses of pIRHN was correlated with the contents of sialic acid in tumor cells, and there was no prominent evidence for the relatedness of the antitumor effect with the expression of p53 and bcl-2. Conclusion: pIRHN may become a new antitumor biological agent.     

Diallyl sulfide induces cell cycle arrest and apoptosis in HeLa human cervical cancer cells through the p53, caspase- and mitochondria-dependent pathways

Diallyl sulfide (DAS), one of the main active constituents of garlic, causes growth inhibition of cancer cells in vitro and promotes immune responses in vivo in experimental settings. However, its effects on the induction of cell cycle and apoptosis in human cervical cancer cells are still unclear. The aims of this study were to explore the anti-cancer effects of DAS in HeLa human cervical cancer cells and to investigate the underlying mechanisms in vitro. Cytotoxicity and apoptosis in HeLa human cervical cancer cells were examined by the morphological changes, viability assay, 4',6-Diamidino-2-phenylindole dihydrochloride (DAPI) staining, comet assay, Western blotting and confocal microscopy examination. The results showed that DAS treatment for 24-72 h resulted in a marked decrease in cell viability time- and dose-dependently. Flow cytometric analysis showed that a 48-h treatment of 75 μM DAS induced G0/G1 cell cycle arrest and sub-G1 phase (apoptosis) in HeLa cells. Typical apoptotic nucleus alterations were observed by fluorescence microscopy in HeLa cells after exposure to DAS using DAPI staining. Cells treated with different concentrations of DAS also showed changes typical of apoptosis such as morphological changes, DNA damage and fragmentation, dysfunction of mitochondria, cytochrome c release and increased expression of pro-caspase-3 and -9. DAS also promoted the release of AIF and Endo G from mitochondria in HeLa cells. In conclusion, DAS induced G0/G1 cell cycle arrest and apoptosis in HeLa cells through caspase- and mitochondria and p53 pathways providing further understanding of the molecular mechanisms of DAS action in cervical cancer. This study, therefore, revealed that DAS significantly inhibits the growth and induces apoptosis of human cervical cancer HeLa cells in vitro.     

Effects of curcumin on proliferation and apoptosis of human cervical carcinoma HeLa cells <Emphasis Type="Italic">in vitro</Emphasis>

Objective: To investigate the regulatory effect of curcumin on profiferation and apoptosis in human cervical carcinoma ceil fine HeLa in vitro. Methods: Human cervical carcinoma cell line Hela was cultured in vitro. HeLa cells were treated with 10-50μmol/L cureumin for 24-72 h and the growth inhibition rates of HeLa ceils were measured by MTT method. Cell apoptosis was inspected by electron microscopy. In addition, the expression of bcl-2, bcl-x1 and caspase-3 protein in HeLa cell were observed by SP immunohistochemistry. Results: Curcumin inhibited the proliferation of HeLa cells on a dose-depending manner.Peak of subG1 appeared on DNA histogram in FCM. A portion of the cells presented the characteristic morphological changes of apoptosis under the electron microscope. The bcl-2, bcl-x1 expression was decreased while Caspase-3 expression was increased. Conclusion:Curcumin could significantly inhibit the growth of HeLa cells; inducing apoptosis through up-regulating Caspase-3 and down-regulating expression of bcl-2 and bcl-x1 was probably one of its molecular mechanisms.     

Aspirin inhibits ErbB2 to induce apoptosis in cervical cancer cells

The use of aspirin is associated with a lower risk of many cancer types. However, there are few reports about cervical cancer. The proto-oncogene ErbB2 is overexpressed in cervical cancer, and considered as a therapeutic target. In the present study, we investigated whether aspirin had therapeutic value in cervical cancer and examined the effects of aspirin on the amplification and expression of ErbB2. To investigate the effects of aspirin on apoptosis and proliferation, we tested apoptosis by Hoechst 33258 staining and Annexin V-FITC/PI method; MTT assay and colony formation assay were used to detect proliferation. Induction of apoptosis and inhibition of proliferation were observed in HeLa cells incubated with aspirin. Western blot and immunocytochemical staining showed that aspirin induced a dose- and time-dependent reduction of ErbB2 expression that was due to proteosome-mediated degradation of this protein. To further investigate the underlying mechanism by which aspirin exerts its apoptosis effects, we studied the ErbB2 downstream cell survival signaling pathways and the expression of anti-apoptosis gene Bcl-2. We found that aspirin inhibited the activation of extracellular signal-regulated kinase (ERK) and AKT. The inhibition of Bcl-2 expression was also observed. These data reveal that aspirin significantly induces apoptosis and inhibits proliferation, which maybe via inhibiting ErbB2 downstream cell survival signaling pathways. Taken together, our article describes a novel mechanism of action for anti-tumor activity of aspirin and implicates aspirin as a novel agent for cervical cancer.     

A novel cromakalim analogue induces cell cycle arrest and apoptosis in human cervical carcinoma HeLa cells through the caspase- and mitochondria-dependent pathway

In the present study, a series of seven synthetic croma-kalim analogues were prepared and evaluated for cytotoxic effect on human cervical carcinoma HeLa cells using WST-8 assay. A preliminary screening of these cromakalim analogues showed that 1-[(3S,4R)-4-(2-ethoxy-4-methyl-1H-pyrrol-1-yl)-3-hydroxy- 2,2-dimethylchroman-6-yl-3-phenylurea (compound?6) had the highest cytotoxic effect (IC50 of 138 μM) and significantly inhibited HeLa cell proliferation after 36 h. In an effort to understand the cytotoxic mechanism of compound?6, we examined its effect on apoptosis and cell cycle distribution. Our results showed that compound 6 induced marked changes in apoptotic morphology and significantly increased early apoptosis of HeLa cells after 48 h by using Annexin V-FITC/PI dual staining assay. This apoptotic induction was associated with an increase in Bax expression, a decrease in Bcl-2 expression, release of cytochrome c and subsequent activation of caspase-9 and -3, which indicated that compound 6 induced apoptosis via caspase- and mitochondria-dependent pathway. By DNA content analysis and [3H]thymidine incorporation assay, compound 6 was found to induce an increase in the number of cells in G1 phase, accompanied by a decrease in the S phase to prevent DNA synthesis after 24 h of treatment. In addition, compound 6 caused significant DNA damage, as detected by the alkaline comet assay. Taken together, the data demonstrate that compound 6 induces apoptosis in HeLa cells through caspase- and mitochondria-dependent pathway and this apoptotic effect is associated with cell cycle arrest and DNA damage. These findings provide further understanding of the molecular mechanisms of compound 6 in cervical cancer.     

Arsenic compounds induce cytotoxicity and apoptosis in cisplatin-sensitive and -resistant gynecological cancer cell lines

PURPOSE: Arsenic compounds have been found to be effective in the treatment of acute promyelocytic leukemia through the downregulation of bcl-2 expression. Resistant ovarian cancer cells often overexpress bcl-2 or p53 proteins or both. We hypothesized that arsenic compounds, such as As2O3 and As2S3, could also be active against gynecological cancers resistant to conventional chemotherapy. METHODS: We investigated the effects of these two arsenic compounds in vitro on ovarian cancer cell lines sensitive (OVCAR, GG, JAM) and resistant (CI80-13S) to cisplatin (CDDP) and on human cervical cancer cell lines (HeLa) in comparison with their effects on human fibroblasts (HF). A fluorometric assay based on measurements of fluorescein diacetate (FDA) in cells was used to determine cell viability. Apoptosis was assessed in terms of cell morphology, by flow cytometry and by a DNA fragmentation assay. RESULTS: Treatment of each cell line with the As2O3 or As2S3 led to a marked dose-dependent decrease in cell growth. The IC50 of the two compounds indicated a significantly greater cytotoxic effect against all the cancer cells tested than against the normal HF. At a clinically achievable concentration (2 microM), As2O3 selectively inhibited the growth and induced apoptosis in CI80-13S, OVCAR and HeLa cells but had no significant apoptotic effect on GG or JAM cells or HF. Following treatment with 5 microM As2S3, the CI80-13S, OVCAR and HeLa cells also exhibited growth inhibition and induction of apoptosis. CONCLUSIONS: Arsenic compounds (As2O3 and As2S3) can inhibit growth and induce apoptosis in human ovarian and cervical cancer cells at clinically achievable concentrations, indicating that As2O3 and As2S3 could be effective in the treatment of gynecological cancer.