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cancers Article Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro Rodolfo Garza-Morales 1,2,† ID , Roxana Gonzalez-Ramos 1,†, Akiko Chiba 3, Roberto Montes de Oca-Luna 2, Lacey R. McNally 4, Kelly M. McMasters 1,5 and Jorge G. Gomez-Gutierrez 1,5,* 1 2 3 4 5 KY 40202, USA * Correspondence: jgguti01@louisville.edu; Tel.: +1-502-852-8464 † These authors contributed equally to this study. Received: 17 April 2018; Accepted: 15 May 2018; Published: 17 May 2018 The Hiram C. Polk Jr., MD, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA; rod.ggarza@gmail.com (R.G.-M.); rgonzalezramos01@bellarmine.edu (R.G.-R.); mcmasters@louisville.edu (K.M.M.) Department of Histology, School of Medicine, Autonomous University of Nuevo Leon, Monterrey, NL 64460, Mexico; rrrmontes@yahoo.com Department of Surgery, School of Medicine, Wake Forest University, Winston-Salem, NC 27109, USA; achiba@wakehealth.edu Department of Cancer Biology, Wake Forest Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC 27109, USA; lacey_mcnally@hotmail.com James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, Abstract: Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer, and treatment is limited to chemotherapy and radiation. Oncolytic virotherapy may be a promising approach to treat TNBC. However, oncolytic adenovirus (OAd)-based mono-therapeutic clinical trials have resulted in modest outcomes. The OAd potency could be increased by chemotherapy-induced autophagy, an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. In this study, the ability of alkylating agent temozolomide (TMZ)-induced autophagy to increase OAd replication and oncolysis in TNBC cells was evaluated. Human TNBC MDA-MB-231 and HCC1937 cells and mouse 4T1 cells were infected with an OAd expressing the red fluorescent protein mCherry on the virus capsid (OAdmCherry) alone or in combination with TMZ. TNBC cells treated with OAdmCherry/TMZ displayed greater mCherry and adenovirus (Ad) early region 1A (E1A) expression and enhanced cancer-cell killing compared to OAdmCherry or TMZ alone. The combined therapy-mediated cell death was associated with virus replication and accumulation of the autophagy marker light chain 3 (LC3)-II. Overall, this study provides experimental evidence of TMZ’s ability to increase oncolytic virotherapy in both human and murine TNBC cells. Keywords: oncolytic; adenovirus; triple-negative; breast cancer; temozolomide; autophagy; virotherapy 1. Introduction Breast cancer is the most common malignancy in women and one of the three most common cancers worldwide [1]. Triple-negative breast cancer (TNBC) accounts for approximately 12–17% of all breast cancers and is more likely to affect younger women, African Americans, Hispanics, and/or those with breast cancer 1 (BRCA1) gene mutations. TNBC is a specific subtype of tumor that lacks the expression of estrogen receptors (ERs), progesterone receptors (PgRs), and human epidermal growth factor receptor type 2 (HER2). As a group, patients with TNBC have a relatively poor prognosis because of an inherently aggressive clinical behavior and a lack of molecular targets for therapy [2,3]. Cancers 2018, 10, 144; doi:10.3390/cancers10050144 www.mdpi.com/journal/cancersPDF Image | Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy
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