Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression.

Ilya Ulasov,Hiroshi Tazawa,Toshiyoshi Fujiwara,Shunsuke Kagawa,Shuhei Osaki,Yasuo Urata,Toshiyuki Kunisada,Toshinori Omori,Yasuaki Yamakawa,Toshifumi Ozaki,Tomohiro Fujiwara,Joe Hasei,Kazuhisa Sugiu,Tadashi Komatsubara,Aki Yoshida

doi:10.1371/journal.pone.0250643

Ilya Ulasov, Hiroshi Tazawa + Show 13 more

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https://doi.org/10.1371/journal.pone.0250643

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Abstract

Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.

Highlights

Soft tissue sarcoma (STS) is a rare cancer that develops from the soft tissues of any part of the body
We have shown that OBP-301 adenoviral E1A suppresses the expression of anti-apoptotic myeloid cell leukemia 1 (MCL1) protein, resulting in the enhancement of apoptosis induced by cisplatin and doxorubicin [17] or zoledronic acid [18]
Calculation of the combination index indicated a synergistic antitumor effect of combination therapy in all STS cell lines, in moderately radiosensitive NMS-2 cells there was an antagonistic effect found with low doses of ionizing radiation and OBP-301 (Fig 1C)

Summary

Introduction

Soft tissue sarcoma (STS) is a rare cancer that develops from the soft tissues of any part of the body. Despite major advances in the treatment of STS poor response to radiotherapy is a critical prognostic factor, and radiotherapyrefractory patients often show tumor recurrence, distant metastasis and poor prognosis [3,4]. Radiosensitizing approaches are required to reduce the dosage of ionizing radiation delivered to STS patients, especially in certain histological subtypes where the response to radiotherapy is known to be limited [7]. STS can be divided into distinct histological subtypes, including fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, Ewing sarcoma, myxosarcoma, peripheral nerve sheath tumor and perivascular wall tumor [8]. Ewing sarcoma is relatively sensitive to radiotherapy compared to other STS tumors, the precise mechanism determining sensitivity or resistance to radiotherapy in this disease remains unknown

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