The role of neoadjuvant chemotherapy in treating advanced epithelial ovarian cancer

Weinberg, Lori; Rodriguez, Gustavo C.; Hurteau, Jean

doi:10.1002/jso.21482

Cited by 24 publications

(21 citation statements)

References 96 publications

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“…Standard first-line chemotherapy is cisplatin-based treatment. However, the majority of ovarian cancer patients who are initially sensitive to cisplatin will eventually relapse, and in many cases acquired resistance will leave no curative treatments (1). The exact mechanisms of cisplatin resistance are not fully understood.…”

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confidence: 99%

Bim Protein Degradation Contributes to Cisplatin Resistance

Wang

Zhou

2011

Journal of Biological Chemistry

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Cisplatin is the first-line chemotherapy for the treatment of several cancers. However, the development of cisplatin resistance represents a major clinical problem, and the mechanisms of acquired resistance are not fully understood. Here we show that degradation of the Bcl-2 homology 3-only proapoptotic protein Bim plays an important role in cisplatin resistance in ovarian cancer. Specifically, we show that treatment of ovarian cancer cells with cisplatin caused Bim phosphorylation and subsequent degradation and that its degradation is associated with cisplatin resistance. We also show that cisplatin treatment caused the activation of ERK, which correlated with Bim phosphorylation and degradation. By inhibiting ERK phosphorylation with the MEK inhibitor and knocking down ERK expression with siRNA, we show that Bim phosphorylation and degradation were blocked, which suggests that Bim is phosphorylated by ERK and that such phosphorylation is responsible for cisplatininduced Bim degradation. We show that ERK was activated in cisplatin-resistant OV433 cells as compared with their counterpart parental OV433 cells. We also show that Bim was phosphorylated and degraded in cisplatin-resistant OV433 cells but not in the parental OV433 cells. Importantly, we show that inhibition of Bim degradation by the proteasome inhibitor MG132 sensitized resistant OV433 cells to cisplatin-induced death. Taken together, our data indicate that degradation of Bim via ERK-mediated phosphorylation can lead to cisplatin resistance. Therefore, these findings suggest that cisplatin resistance can be overcome by the combination of cisplatin and the proteasome inhibitors in ovarian cancer cells.Ovarian cancer is the fifth leading cause of cancer-related deaths in women in the United States. Currently available therapeutic options include tumor debulking surgery and chemotherapy. Standard first-line chemotherapy is cisplatin-based treatment. However, the majority of ovarian cancer patients who are initially sensitive to cisplatin will eventually relapse, and in many cases acquired resistance will leave no curative treatments (1). The exact mechanisms of cisplatin resistance are not fully understood.There are many molecules and pathways that have been shown to contribute to cisplatin resistance (2-10). Deregulation of these proteins results in a variety of consequences, including insufficient DNA binding, increased DNA repair, and altered expression of genes involved in the cell death and survival pathways (9, 11). Among survival pathways, activation of ERK contributes to cisplatin resistance (12). ERK is a member of the MAPK family that can be activated by growth signals (13). ERK is activated by MEK through a cascade of upstream kinases involving ras and raf (14). Once it is activated, ERK translocates into the nucleus to influence cellular responses via phosphorylation, leading to a number of cell processes, including cell proliferation and cell survival (14). There are many substrates that can be phosphorylated by ERK, including transcription...

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confidence: 99%

Bim Protein Degradation Contributes to Cisplatin Resistance

Wang

Zhou

2011

Journal of Biological Chemistry

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“…In our study, intraperitoneal administration of chemotherapy before surgery for ovarian peritoneal carcinomatosis is an innovative and attractive procedure. The therapeutic sequence allows extending the loco-regional time action without morbidity associated from the early postoperative period or the inconvenience from the latest adherent postoperative syndrome, as well as increasing the benefits offered by neoadjuvant chemotherapy to the optimization of surgery [16] . We selected Paclitaxel by its well known antineoplasic activity opposed to ovarian carcinoma, excellent pharmacokinetics when administered intraperitoneally, and the potential weekly administration [17,18].…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant intraperitoneal chemotherapy with paclitaxel for the radical surgical treatment of peritoneal carcinomatosis in ovarian cancer: a prospective pilot study

Muñoz-Casares

Rufián

Arjona‐Sánchez

et al. 2011

Cancer Chemother Pharmacol

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“…Generally, a median of three/four cycles of NAC are provided in literature. In our protocol we planned six cycles of NAC, as advised by some authors, in order to maximize these effects, and reduce as much as possible the extent of peritoneal disease before surgical approach [38]. Indeed, in about one third of patients in group A no peritoneal nodules were found, and the Journal of Surgical Oncology Fig.…”

Section: Discussionmentioning

confidence: 99%