β-Adrenergic Receptor Inhibitor and Oncolytic Herpesvirus Combination Therapy Shows Enhanced Antitumoral and Antiangiogenic Effects on Colorectal Cancer

Jiali Hu; Jiali Hu; Jiali Hu; Cuiyu Chen; Cuiyu Chen; Ruitao Lu; Yu Zhang; Yu Zhang; Yang Wang; Yang Wang; Qian Hu; Qian Hu; Wanting Li; Wanting Li; Shiyu Wang; Shiyu Wang; Ouyang Jing; Ouyang Jing; Hanying Yi; Hanying Yi; Wei Zhang; Wei Zhang; Ling Chen; Weihua Huang; Weihua Huang; Weihua Huang; Jia Luo; Howard L. McLeod; Howard L. McLeod; Howard L. McLeod; Ran Xu; Yijing He; Yijing He; Yijing He

doi:10.3389/fphar.2021.735278

Frontiers in Pharmacology (Oct 2021)

β-Adrenergic Receptor Inhibitor and Oncolytic Herpesvirus Combination Therapy Shows Enhanced Antitumoral and Antiangiogenic Effects on Colorectal Cancer

Jiali Hu,
Jiali Hu,
Jiali Hu,
Cuiyu Chen,
Cuiyu Chen,
Ruitao Lu,
Yu Zhang,
Yu Zhang,
Yang Wang,
Yang Wang,
Qian Hu,
Qian Hu,
Wanting Li,
Wanting Li,
Shiyu Wang,
Shiyu Wang,
Ouyang Jing,
Ouyang Jing,
Hanying Yi,
Hanying Yi,
Wei Zhang,
Wei Zhang,
Ling Chen,
Weihua Huang,
Weihua Huang,
Weihua Huang,
Jia Luo,
Howard L. McLeod,
Howard L. McLeod,
Howard L. McLeod,
Ran Xu,
Yijing He,
Yijing He,
Yijing He

Affiliations

Jiali Hu: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Jiali Hu: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Jiali Hu: Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
Cuiyu Chen: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Cuiyu Chen: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Ruitao Lu: School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
Yu Zhang: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Yu Zhang: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Yang Wang: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Yang Wang: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Qian Hu: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Qian Hu: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Wanting Li: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Wanting Li: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Shiyu Wang: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Shiyu Wang: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Ouyang Jing: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Ouyang Jing: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Hanying Yi: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Hanying Yi: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Wei Zhang: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Wei Zhang: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Ling Chen: Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
Weihua Huang: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Weihua Huang: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Weihua Huang: Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
Jia Luo: Department of Hepatobiliary and Intestinal Surgery, Hunan Cancer Hospital, Changsha, China
Howard L. McLeod: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Howard L. McLeod: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Howard L. McLeod: Geriatric Oncology Consortium, Tampa, FL, United States
Ran Xu: Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, China
Yijing He: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
Yijing He: Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
Yijing He: School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China

DOI: https://doi.org/10.3389/fphar.2021.735278
Journal volume & issue: Vol. 12

Abstract

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Oncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, despite the development of novel OVs with improved efficacy and tumor selectivity, their limited efficacy as monotherapeutic agents remains a significant challenge. This study extended our previously observed combination effects of propranolol, a nonselective β-blocker, and the T1012G oncolytic virus into colorectal cancer models. A cell viability assay showed that cotreatment could induce synergistic killing effects on human and murine colorectal cell lines. Moreover, cotreatment caused sustained tumor regression compared with T1012G monotherapy or propranolol monotherapy in human HCT116 and murine MC38 tumor models. The propranolol activity was not via a direct effect on viral replication in vitro or in vivo. Western blotting showed that cotreatment significantly enhanced the expression of cleaved caspase-3 in HCT116 and MC38 cells compared with the propranolol or T1012G alone. In addition, propranolol or T1012G treatment induced a 35.06% ± 0.53% or 35.49% ± 2.68% reduction in VEGF secretion in HUVECs (p < 0.01/p < 0.01). Cotreatment further inhibited VEGF secretion compared with the monotherapies (compared with propranolol treatment: 75.06% ± 1.50% decrease, compared with T1012G treatment: 74.91% ± 0.68%; p＜0.001, p < 0.001). Consistent with the in vitro results, in vivo data showed that cotreatment could reduce Ki67 and enhance cleaved caspase 3 and CD31 expression in human HCT116 and murine MC38 xenografts. In summary, β-blockers could improve the therapeutic potential of OVs by enhancing oncolytic virus-mediated killing of colorectal cancer cells and colorectal tumors.

Published in Frontiers in Pharmacology

ISSN: 1663-9812 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://journal.frontiersin.org/journals/pharmacology

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