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Cancers 2018, 10, 144 10 of 15 3. Discussion Oncolytic virotherapy is an emerging treatment modality for the treatment of advanced solid tumors refractory to current therapies. However, OAd’s used as monotherapy have shown limited therapeutic effects because their efficacy has been limited to oncolytic cell death. Therefore, combining oncolytic Ad’s with other treatment is mandatory to achieve their full potential. In the present study, using the human TNBC cell lines HCC1937 and MDA-MB-231 and murine TNBC cell line 4T1, we demonstrated that combining OAdmCherry with the alkylating agent TMZ led to an enhanced OAd infection and oncolysis, which was associated with increased autophagosome formation and accumulation of LC3-II. The mechanism of TMZ-induced increase in Ad replication is not elucidated in the current study, and further research is necessary to determine the role of autophagy in the observed increased Ad replication and oncolysis. TNBC is one of the most aggressive and complicated types of breast cancer to treat. Chemotherapy remains to this day the standard therapeutic approach for TNBC at all stages. However, many tumors are highly resistant to chemotherapy, causing patients to relapse quickly after treatment; this is mostly because of genomic and chromosomal instability present in TNBC. Therefore, a combination therapy involving several treatment modalities that can surpass this difficulty and reduce the dose of chemotherapeutic drugs while maintaining therapeutic efficacy is more likely to have success in the clinic [29]. There have been various advances to enhance oncolytic virotherapy using different chemotherapeutic drugs, radiotherapy, and immune-checkpoint inhibitors [30]. A wide range of clinical and pre-clinical studies have shown that combining different treatment modalities has resulted in in vitro and in vivo synergies through various mechanisms of cell death. Synergy has been recorded between the alkylating agent TMZ and OAd in various types of cancer, such as in advanced glioma [31–34]. Previously, it was reported that the MDA-MB-436 human TNBC cell line, when treated with a triple combination of TMZ; 4-hydroperoxycyclophosphamide (4-HPCP); an active metabolite of the prodrug cyclophosphamide (CP); and Ad5/3-D24-GMCSF, a 5/3-capsid chimeric OAd coding for GM-CSF, had increased immunogenic cell killing and autophagy [31]. In another study, it was reported that CP at low doses increased the efficacy of Ad5/3-DM4-GMCSF in MDA-MB-436 cells, and similar effects were observed in an orthotopic TNBC xenograft mouse model [35]. Autophagy plays a critical role on OAd-mediated CPE in cancer cells. The basic mechanism of autophagy involves cell degradation of unnecessary or dysfunctional cellular components. Autophagy has dual roles, acting as a survival mechanism and as a caspase-independent form of programmed cell death [14]. Previously, it was reported that OAd induces autophagy by increasing the conversion of LC3-I to LC3-II. Additionally, the inhibition of autophagy with 3-MA resulted in a decreased expression of adenoviral proteins and viral replication, and the induction of autophagy with rapamycin increased OAd replication [16]. In contrast, other studies have shown that deletion of 24 amino acids in the E1A gene and with the tripeptide Arg-Gly-Asp (Delta-24-RGD), an OAd whose infectivity in cancer cells is enhanced through the insertion of a RGD-4C motif in the high affinity (HI) loop of the adenoviral fiber protein, and OBP-405, an OAd regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad, OBP-301) with a tropism modification (RGD), induced the autophagic cell death of glioblastoma cells, whereas autophagy inhibitors did not affect the replication of Delta-24-RGD and OBP-405 [36,37]. We recently found that TMZ is able to render murine and human lung cancer cells susceptible to oncolytic virotherapy. The enhanced killing effect induced by TMZ and Adhz60 (E1b deleted Ad serotype 5) was due to productive virus replication and autophagy induction [26,27]. In addition, the OAd used in the previous studies was demonstrated to be safe for normal human and mouse cell lines. In this study, we confirmed that TMZ treatment sensitizes murine cancer cells, particularly 4T1 TNBC cells, and represents an animal stage IV human breast cancer model. Therefore, this syngeneic mouse model has significant clinical relevance because it mimics the clinical situation of TNBC patients.PDF Image | Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy
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