Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the HER-2 correlates with drug-resistance and a poor prognosis in breast cancer, however the mechanism(s) of HER-2-mediated drug-resistance are unknown. We examined the effects of antisense Bcl-2 and HER-2 oligonucleotides (ODN) to assess the mechanism(s) through which down-regulation of Bcl-2 and HER-2 enhances drug-sensitivity. Using two human breast cancer cell lines, MDA-MB-231 and BT-474, the antitumor effects of a combination of antisense ODN and anticancer drugs, including mitomycin C (MMC), adriamycin (ADM), paclitaxel (TXL), and docetaxel (TXT) was evaluated. The expression of Bcl-2 protein was suppressed by treatment with antisense Bcl-2 ODN in a dose-dependent manner. An enhanced drug-sensitivity to MMC and TXL upon pretreatment with antisense Bcl-2 ODN was observed, with the IC50 values increasing 1.9- and 2.0-fold, respectively. Treatment of BT-474 cells with antisense HER-2 at 1.0 micro M suppressed HER-2 overexpression by 60.5%. Pretreatment with antisense HER-2 ODN increased the sensitivity of these cells to ADM and TXL 20.8- and 10.8-fold, respectively. In vivo experiments using a combination of antisense HER-2 and TXL showed the similar enhancement of antitumor effect of TXL as compared to that of antisense HER-2 or TXL alone (p=0.068). Enhancement of drug-sensitivity was associated with the induction of apoptosis. Of interest, treatment with antisense HER-2 ODN also suppressed the expression of Bcl-2 and pAkt. These results indicate that down-regulation of Bcl-2 and HER-2 increased drug-sensitivity by modulating drug-induced apoptotic pathways in breast cancer cells, and that antisense ODN therapy, targeting Bcl-2 and HER-2 may be a useful strategy to enhance drug-sensitivity.
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PMID:Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs. 1263 82

Although attempts have been made to treat undifferentiated thyroid carcinoma using multidisciplinary therapeutic procedures including surgery, radiotherapy, and chemotherapy, the prognosis of undifferentiated thyroid carcinoma remains quite poor. New approaches to increase the sensitivity of patients to anticancer drugs and radiation will be needed to improve the survival rate for undifferentiated thyroid carcinoma. We examined the effect of Bcl-2 antisense oligonucleotide on drug-sensitivity in association with apoptosis in the 8305C undifferentiated thyroid carcinoma cell line. The drug sensitivity was evaluated by MTT assay for 48 h, while apoptosis was assessed according to the formation of internucleosomal DNA ladders. The Bcl-2 antisense was introduced into 8305C cells by using a 18-mer phosphorothioate oligonucleotide by lipopolyamine-mediated transfection twice for 12 h. The expression of apoptosis genes was assessed by Western blotting. The 8305C cells were sensitive to adriamycin (ADM), mitomycin (MMC), docetaxel (TXT), and paclitaxel (TXL), showing mean IC50 values of 0.72, 1.1, 1.3, and 4.1 microM, respectively. In contrast, the 8305C cells were resistant to cisplatin (CDDP) and 5-fluorouracil (5-FU), with mean IC50 values of 42.0 and 48.0 microM, respectively. Treatment with Bcl-2 antisense suppressed the protein level of Bcl-2 in 8305C cells in a dose-dependent manner up to 1.0 microM. Drug-sensitivity was increased by pretreatment with Bcl-2 antisense as assessed by the IC50 (x-fold): 0.48 (1.5-fold) in ADM; 0.42 (2.6-fold) in MMC, 0.56 (2.3-fold) in TXT, 1.5 (2.7-fold) in TXL, 8.6 (4.9-fold) in CDDP, and 25.0 (1.9-fold) in 5-FU, respectively. The increased drug-sensitivity was associated with the induction of apoptosis-related proteins, Fas, caspase 8, cytochrome c, caspase 3, and to subsequent apoptosis, as determined by the formation of internucleosomal DNA ladders and PARP in the treated cells. Susceptibility in apoptotic cell death following treatment with anticancer drugs was associated with induction of apoptosis-related genes in undifferentiated thyroid carcinoma cells, and induction of apoptosis was enhanced by pretreatment with Bcl-2 antisense oligonucleotide. These results imply a potential new strategy targeting an antiapoptotic protein, Bcl-2, by its antisense oligonucleotide for enhancement of chemotherapeutic efficacy in undifferentiated thyroid carcinomas.
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PMID:Effect of Bcl-2 antisense oligonucleotide on drug-sensitivity in association with apoptosis in undifferentiated thyroid carcinoma. 1273 25

Since the survival benefit of tamoxifen (TAM) combined with anticancer drugs in treating node- and receptor-positive breast cancer is small, appropriate treatment schedules and the rationale for the combination remains unclear. We examined the effect of estradiol (E2) on sensitivity to anticancer drugs to clarify the survival benefit of tamoxifen combined with anticancer drugs. We used the MTT assay to assess the effect of E2 on sensitivity to anticancer drugs in the E2 receptor-positive and -negative breast cancer cell lines, MCF-7 and MDA-MB-231, respectively. We assessed the expression of apoptosis-related proteins by Western blotting, and evaluated apoptosis using the TUNEL method. Serum levels of E2 were measured using an enzyme-labeled radioimmunoassay in patients with premenopausal breast cancer before and during treatment with tamoxifen. Estrogen administration decreased sensitivity in MCF-7 cells to the anticancer drugs, adriamycin (ADM), mitomycin C (MMC), and paclitaxel (TXL), evaluated as increases in the IC50 values for ADM (4.1-fold), MMC (1.9-fold) and TXL (13.0-fold), compared with those of each drug alone. Estradiol in MDA-MB-231 cells similarly increased the IC50 values for ADM (9.5-fold), MMC (15.6-fold), and TXL (2.4-fold). The decreased sensitivity to these anticancer drugs was associated with the attenuation of apoptosis. Estrogen dose-dependently increased the expression of Bcl-2 protein in MCF-7, but not in MDA-MB-231 cells, and suppressed the expression of Bax and cytochrome c induced by anticancer drugs in association with decreased apoptosis compared with the effect of each drug alone. Phosphorylation of the Bcl-2 protein induced by TXL was decreased in the presence of E2 in MCF-7 cells. Serum levels of E2 were increased in 5 patients without amenorrhea and in 1 patient with amenorrhea after treatment with TAM alone in adjuvant therapy, compared with levels before treatment. Estradiol decreased sensitivity to ADM, MMC, and TXL in MCF-7 and MDA-MB-231 breast cancer cells, and this was associated in part with an increase in the amount of Bcl-2 protein, and decreases in levels of Bax and cytochrome c leading to apoptosis. These results suggest that therapy with TAM and anticancer drugs should be sequentially scheduled with anticancer drugs followed by TAM in an adjuvant setting to treat patients with breast cancer for a potentially improved survival benefit.
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PMID:Rationale for sequential tamoxifen and anticancer drugs in adjuvant setting for patients with node- and receptor-positive breast cancer. 1575 98

Cisplatin is one of the most commonly used drugs in the treatment of gastric cancer. However, drug resistance is a major obstacle for effective treatment and originates in multiple mechanisms such as enhanced DNA repair and anti-apoptosis. Our previous results demonstrated that XRCC1 was a key regulator of cisplatin induced DNA damage and apoptosis. TXNL1, a member of the thioredoxin family, negatively regulated the expression of XRCC1 via the ubiquitin-proteasome pathway. Here, we investigated the role of TXNL1 in the apoptosis induced by cisplatin. Our data showed that the expression of TXNL1 in the cisplatin resistant gastric cancer cell lines BGC823/DDP and SGC7901/DDP cells was significantly lower compared with the cisplatin sensitive cell lines BGC823 and SGC7901. Inhibition of the expression of TXNL1 in BGC823 and SGC7901 cells led to increased resistance to cisplatin induced apoptosis and cell death detected by Tunel and clonogenic assay, respectively. In contrast, over expression of TXNL1 in BGC823/DDP and SGC7901/DDP cells lead to higher cisplatin induced apoptosis and cell death. Moreover, our results demonstrated that the mechanism of TXNL1 regulating cisplatin-induced apoptosis was closely associated with Bcl-2 mediated mitochondria apoptosis pathway. In conclusion, these findings suggest that TXNL1 was a feasible modulator and potential chemotherapeutic target for the cisplatin resistant phenotype of human gastric cancer cells.
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PMID:TXNL1 induces apoptosis in cisplatin resistant human gastric cancer cell lines. 2534 20