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Bcl - 2 confers survival in cisplatin treated cervical cancer cells : circumventing cisplatin dose - dependent toxicity and resistance

dc.contributor.authorLeisching, Gina
dc.contributor.authorLoos, Benjamin
dc.contributor.authorBotha, Matthys
dc.contributor.authorEngelbrecht, Anna‑Mart
dc.contributor.otherPhysiological Sciencesen_ZA
dc.date.accessioned2015-10-29T09:05:11Z
dc.date.available2015-10-29T09:05:11Z
dc.date.issued2015
dc.identifier.citationLeisching, G., Loos, B., Botha, M., Engelbrecht, A. 2015. Bcl - 2 confers survival in cisplatin treated cervical cancer cells : circumventing cisplatin dose - dependent toxicity and resistance. Journal of translational medicine, 13(328), DOI 10.1186/s12967-015-0689-4en_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/97603
dc.descriptionPublication of this article was funded by the Stellenbosch University Open Access Fund.
dc.description.abstractAbstract Background: Cisplatin is the main chemotherapeutic drug for the treatment of cervical cancers, however resistance to cisplatin is increasingly common and therefore has limited the efficacy and use of this drug in the clinic. Dosedependent toxicity poses an additional challenge since patients suffer long-term and often permanent side-effects after treatment. Bcl-2 up-regulation has been implicated in the resistance to cisplatin in a variety of cancer cell lines, however its role in cervical cancer is confounding. Methods: A low, non-cytotoxic concentration of cisplatin was used in the treatment of HeLa and CaSki cells. Bcl-2 expression was determined through Western blotting and immunocytochemistry before and after treatment with cisplatin. To assess the reliance of the cervical cancer cells on Bcl-2 in the presence of cisplatin, Bcl-2 knock-down was achieved through RNA interference, where after apoptosis was assessed through PARP cleavage (Western blotting), Caspase activity (Caspase-Glo©) and PI inclusion analysis (Flow cytometry). Finally, pre-malignant and malignant cervi‑ cal tissue was analysed for the presence of Bcl-2 through Western blotting and immunofluorescence. Results: Cervical cancer cells upregulate Bcl-2 when treated with a non-cytotoxic concentration of cisplatin, which when silenced, effectively enhanced cisplatin sensitivity, and therefore significantly induced apoptosis. Analysis of the expression profile of Bcl-2 in cervical tissue revealed its up-regulation in cervical carcinoma, which agrees with results obtained from the in vitro data. Conclusions: Our data strongly suggest that utilising a lower dose of cisplatin is feasible when combined with Bcl-2 silencing as an adjuvant treatment, thereby improving both the dose-dependent toxicity, as well as cervical cancer resistance. Keywords: Bcl-2, Beclin-1, Cisplatin, Cervical cancer, Apoptosis
dc.description.urihttp://www.translational-medicine.com/content/pdf/s12967-015-0689-4.pdfen_ZA
dc.publisherBioMed Centralen_ZA
dc.subjectBcl ‑ 2en_ZA
dc.subjectBeclin ‑ 1en_ZA
dc.subjectCisplatinen_ZA
dc.subjectCervical canceen_ZA
dc.subjectApoptosisen_ZA
dc.titleBcl - 2 confers survival in cisplatin treated cervical cancer cells : circumventing cisplatin dose - dependent toxicity and resistanceen_ZA
dc.typeArticleen_ZA
dc.description.versionBackground: Cisplatin is the main chemotherapeutic drug for the treatment of cervical cancers, however resistance to cisplatin is increasingly common and therefore has limited the efficacy and use of this drug in the clinic. Dosedependent toxicity poses an additional challenge since patients suffer long-term and often permanent side-effects after treatment. Bcl-2 up-regulation has been implicated in the resistance to cisplatin in a variety of cancer cell lines, however its role in cervical cancer is confounding. Methods: A low, non-cytotoxic concentration of cisplatin was used in the treatment of HeLa and CaSki cells. Bcl-2 expression was determined through Western blotting and immunocytochemistry before and after treatment with cisplatin. To assess the reliance of the cervical cancer cells on Bcl-2 in the presence of cisplatin, Bcl-2 knock-down was achieved through RNA interference, where after apoptosis was assessed through PARP cleavage (Western blotting), Caspase activity (Caspase-Glo©) and PI inclusion analysis (Flow cytometry). Finally, pre-malignant and malignant cervical tissue was analysed for the presence of Bcl-2 through Western blotting and immunofluorescence. Results: Cervical cancer cells upregulate Bcl-2 when treated with a non-cytotoxic concentration of cisplatin, which when silenced, effectively enhanced cisplatin sensitivity, and therefore significantly induced apoptosis. Analysis of the expression profile of Bcl-2 in cervical tissue revealed its up-regulation in cervical carcinoma, which agrees with results obtained from the in vitro data. Conclusions: Our data strongly suggest that utilising a lower dose of cisplatin is feasible when combined with Bcl-2 silencing as an adjuvant treatment, thereby improving both the dose-dependent toxicity, as well as cervical cancer resistance.en_ZA


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