RESUMO
OBJECTIVE: Patients with epithelial ovarian cancers experience the highest fatality rates among all gynecological malignancies which require development of novel treatment strategies. Tumor cell necrosis was previously reported in a number of cancer cell lines following treatment with a p53-derived anti-cancer peptide called PNC-27. This peptide induces necrosis by transmembrane pore formation with HDM-2 protein that is expressed in the cancer cell membrane. We aimed to extend these studies further by investigating expression of membrane HDM-2 protein in ovarian cancer as it relates to susceptibility to PNC-27. PROCEDURES: Herein, we measured HDM-2 membrane expression in two ovarian cancer cell lines (SKOV-3 and OVCAR-3) and a non-transformed control cell line (HUVEC) by flow cytometric and western blot analysis. Immunofluorescence was used to visualize colocalization of PNC-27 with membrane HDM-2. Treatment effects with PNC-27 and control peptide were assessed using a MTT cell proliferation assay while direct cytotoxicity was measured by lactate dehydrogenase (LDH) release and induction of apoptotic markers; annexin V and caspase-3. RESULTS: HDM-2 protein was highly expressed and frequently detected in the membranes of SKOV-3 and OVCAR-3 cells; a prominent 47.6 kDa HDM-2 plasma membrane isoform was present in both cell lines whereas 25, 29, and 30 kDa isoforms were preferentially expressed in OVCAR-3. Notably, PNC-27 colocalized with HDM-2 in the membranes of both cancer cell lines that resulted in rapid cellular necrosis. In contrast, no PNC-27 colocalization and cytotoxicity was observed with non-transformed HUVEC demonstrating minimal expression of membrane HDM-2. CONCLUSIONS: Our results suggest that HDM-2 is highly expressed in the membranes of these ovarian cancer cell lines and colocalizes with PNC-27. We therefore conclude that the association of PNC-27 with preferentially expressed membrane HDM-2 isoforms results in the proposed model for the formation of transmembrane pores and epithelial ovarian cancer tumor cell necrosis, as previously described in a number of solid tissue and hematologic malignancies.
Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/farmacologia , Anexina A5/análise , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/metabolismo , Caspase 3/análise , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , L-Lactato Desidrogenase/análise , Necrose/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Recent advances in biomedical research in cancer immunotherapy have identified the use of an oxidative stress-based approach to treat cancers, which works by inducing immunogenic cell death (ICD) in cancer cells. Since the anti-cancer effects of non-thermal plasma (NTP) are largely attributed to the reactive oxygen and nitrogen species that are delivered to and generated inside the target cancer cells, it is reasonable to postulate that NTP would be an effective modality for ICD induction. NTP treatment of tumors has been shown to destroy cancer cells rapidly and, under specific treatment regimens, this leads to systemic tumor-specific immunity. The translational benefit of NTP for treatment of cancer relies on its ability to enhance the interactions between NTP-exposed tumor cells and local immune cells which initiates subsequent protective immune responses. This review discusses results from recent investigations of NTP application to induce immunogenic cell death in cancer cells. With further optimization of clinical devices and treatment protocols, NTP can become an essential part of the therapeutic armament against cancer.
RESUMO
BACKGROUND: Pancreaticoduodenectomy (PD) with right hemicolectomy (RH) to treat locally advanced right colon cancer (LARCC) has been rarely reported in the literature. Herein, we characterize clinicopathologic factors and evaluate outcomes of en bloc PD and RH for LARCC. METHODS: A systematic review of the literature was conducted on PubMed using MeSH terms ("pancreaticoduodenectomy" or "pancreas/surgery" or "duodenum/surgery" or "colectomy") and ("colonic neoplasms"). Data was extracted from patients who underwent en bloc PD and RH for LARCC. Factors investigated included patient demographics, surgical and pathologic parameters, postoperative complications, disease recurrence, and survival. RESULTS: Our search yielded 27 articles (106 patients), including 1 case from our institution. Most patients were male (62.1%), median age 58 years (range 34-83). Surgical procedures performed included en bloc RH with PD (n = 91, 85.8%) and en bloc RH with pylorus-preserving PD (n = 15, 14.2%). Among reported, 95.5% of patients (n = 63), underwent R0 resection. One or more complications were reported in 33 patients (52.4%). Median survival was 168 months. Survival after resection was 75.9% at 2 years and 66.3% at 5 years. Overall survival was greater in patients with no lymph node involvement (IIC versus IIIC, hazard ratio 8.4, P = .003). Five-year survival for patients was 84.9% in patients with stage IIC versus 46.4% in patients with stage IIIC. There were 3 postoperative mortalities. CONCLUSION: This data demonstrates that en bloc PD and RH is rarely performed yet can be a potentially safe treatment option in patients with LARCC. Lymph node involvement was the only independent prognostic factor.