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Cancers 2018, 10, 144 2 of 15 Cytotoxic chemotherapy is the primary treatment option for patients with TNBC in both early and advanced stages of the disease [3]. Studies of neoadjuvant chemotherapy with agents such as taxanes and anthracyclines have consistently reported high response rates, but despite optimal systemic chemotherapy, fewer than 30% of women with metastatic breast cancer survive longer than 5 years from diagnosis, and virtually all women with metastatic TNBC will ultimately die of their disease [4–6]. Therefore, an alternative approach that selectively targets cancer cells while sensitizing TNBC to chemotherapy must be developed. One of the most promising approaches for the treatment of malignant tumors is the use of oncolytic adenovirus (OAd). OAd’s are modified to replicate, spread, and induce oncolytic cell death in cancer cells but not in normal cells [7]. However, many clinical trials have revealed that monotherapy with OAd shows limited therapeutic effects, as its efficacy has been limited to oncolytic cell death [8]. For this reason, a combined therapy composed of OAd’s and other treatment modalities with different mechanisms of cell death is more likely to have success in the clinic. Several preclinical and clinical studies have demonstrated that OAd’s produce synergistic antitumor effects in combination with other treatment modalities, such as radiotherapy and chemotherapeutic agents [9–13]. Autophagy is the mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. The breakdown of cellular components can ensure cellular survival during starvation and stress by maintaining cellular energy levels. Autophagy has a dual role, acting as a survival mechanism and as a caspase-independent form of programmed cell death [14,15]. We have shown that OAd induces autophagy in lung cancer cells and that autophagy inhibition with 3-methyladenine (3-MA), an autophagy inhibitor, decreases viral replication, whereas rapamycin, an autophagy inducer, increases OAd replication [16]. Temozolomide (TMZ) is a second-generation imidazotetrazine pro-drug that undergoes spontaneous conversion under physiological conditions to the active alkylating agent 5-(3-dimethyl-1-triazenyl) imidazole-4-carboxamide (MTIC) [17]. TMZ has been used for the treatment of a variety of malignancies, such as glioblastoma multiforme, astrocytoma, non-small cell lung carcinoma, melanoma, and breast cancer [18–21]. Several studies have demonstrated that TMZ-induced autophagy can enhance oncolytic virotherapy in melanoma and glioblastoma xenograft models [22–25]. We recently found that TMZ-induced autophagy enhanced OAd replication and oncolysis in human lung cancer cell lines and that the combination treatment led to a synergistic cancer-cell killing effect. Moreover, the combined therapy of OAd with TMZ resulted in superior lung tumor suppression in vivo over that of either treatment alone. Our data indicated that the enhanced anti-tumor activity was at least in part due to an OAd-mediated cytopathic effect (CPE), apoptosis, and autophagy induction [26]. More importantly, TMZ did not increase virus replication and oncolysis in human and mouse non-cancerous lung cells. This suggests that a combined therapy approach is safe for non-cancerous cells [27]. In the current study, we evaluated whether alkylating agent TMZ-induced autophagy enhances OAd replication and oncolysis in human and mouse TNBC cells as well as the cell death mechanisms of the combined treatment. Our results indicate that TMZ enhances OAd replication and oncolysis in TNBC cells. We also show that an increase in autophagy induction is associated with an increase in TNBC oncolytic cell death. 2. Results 2.1. Evaluation of OAd-Mediated CPE and TMZ-Induced Cytotoxicity in Human TNBC Cells Human TNBC cell lines MDA-MB-231 and HCC1937 were infected with an OAd expressing mCherry (OAdmCherry) or a replication-deficient adenovirus expressing green fluorescent protein (AdGFP). At 72 h post infection, in both cell lines, crystal violet staining revealed that an OAdmCherry-mediated CPE increased in a virus-dose-dependent manner. In contrast, AdGFP-treated cells did not induce CPE, even at the highest multiplicity of infection (MOI) concentration of 20PDF Image | Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy
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