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\begin{document}

\title{\selectlanguage{greek}β-\selectlanguage{english}adrenergic receptor inhibitor and oncolytic herpesvirus combination
therapy shows enhanced antitumoral and antiangiogenic effects on
colorectal cancer\selectlanguage{english}}



\author[1]{Jiali Hu}%
\author[1]{Cuiyu Chen}%
\author[2]{Ruitao Lu}%
\author[1]{Qian Hu}%
\author[1]{Yang Wang}%
\author[1]{Wanting Li}%
\author[1]{Ouyang Jing}%
\author[1]{Hanying Yi}%
\author[3]{Wei Zhang}%
\author[4]{Ling Chen}%
\author[1]{Weihua Huang}%
\author[5]{Jia Luo}%
\author[6]{Howard McLeod}%
\author[1]{Yijing He}%
\affil[1]{1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; 2Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China; 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China;}%
\affil[2]{School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong,China;}%
\affil[3]{Institute of Clinical Pharmacology}%
\affil[4]{Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China;}%
\affil[5]{Department of Hepatobiliary and Intestinal Surgery，Hunan Cancer Hospital, Changsha, Hunan, China;}%
\affil[6]{1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; 2Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China; 6USF Taneja College of Pharmacy, Tampa, Florida, USA}%


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  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
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. In this study,
we explored the effect of propranolol, a nonselective \selectlanguage{greek}β-\selectlanguage{english}blocker, on the
antitumor efficacy of the T1012G virus in 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. Additionally, propranolol treatment did not produce a
positive 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\% \selectlanguage{ngerman}± 0.53\% or 35.49\% ± 2.68\% reduction in
VEGF secretion in HUVECs (P\selectlanguage{english}<0.01/P\selectlanguage{english}<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\selectlanguage{english}<0.001, P\selectlanguage{english}<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, \selectlanguage{greek}β-\selectlanguage{english}blockers could improve the
therapeutic potential of OVs by enhancing oncolytic virus-mediated
killing of colorectal cancer cells and antiangiogenic effects on
colorectal tumors.%
\end{abstract}%



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\textbf{Hosted file}

\verb`Manuscript.doc`  available at \url{https://authorea.com/users/728903/articles/709679-%CE%B2-adrenergic-receptor-inhibitor-and-oncolytic-herpesvirus-combination-therapy-shows-enhanced-antitumoral-and-antiangiogenic-effects-on-colorectal-cancer}

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