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. 2020 Feb;13(2):393-400.
doi: 10.1016/j.tranon.2019.10.005. Epub 2019 Dec 30.

Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model

Kentaro Igarashi  1 , Kei Kawaguchi  2 , Ming Zhao  3 , Tasuku Kiyuna  2 , Kentaro Miyake  2 , Masuyo Miyake  2 , Scott D Nelson  4 , Sarah M Dry  4 , Yunfeng Li  4 , Norio Yamamoto  5 , Katsuhiro Hayashi  5 , Hiroaki Kimura  5 , Shinji Miwa  5 , Takashi Higuchi  1 , Shree Ram Singh  6 , Hiroyuki Tsuchiya  7 , Robert M Hoffman  8
Affiliations

Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model

Kentaro Igarashi et al. Transl Oncol. 2020 Feb.

Abstract

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential.

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Figures

Figure 1
Figure 1
Effect of caffeine (CAF) and valproic acid (VPA) on adult pleomorphic RMS cell in culture. Growth inhibitory activity of CAF and VPA or their combination against an adult pleomorphic rhabdomyosarcoma cell line AC-RMS01.
Figure 2
Figure 2
Fluorescence imaging of Salmonella typhimurium A1-R-GFP. Fluorescence confocal imaging of S. typhimurium A1-R-GFP targeting the adult pleomorphic RMS PDOX. Bars: 12.5 μm.
Figure 3
Figure 3
Fluorescence of Salmonella typhimurium A1-R-GFP targeting the adult pleomorphic RMS PDOX. (A) Fluorescence intensity of S. typhimurium A1-R-GFP on the adult pleomorphic RMS PDOX. (B) Fluorescence area of S. typhimurium A1-R-GFP on the adult pleomorphic RMS PDOX.
Figure 4
Figure 4
(A) Treatment scheme. (B) Efficacy of cyclophosphamide (CPA), VPA combined with CAF, Salmonella typhimurium A1-R (A1-R) and A1-R combined with VPA and CAF on the adult pleomorphic rhabdomyosarcoma PDOX. *P < 0.0001. Tumor volume was measured at the indicated time points after the onset of treatment. n = 8 mice/group.
Figure 5
Figure 5
Tumor histology. H & E-stained section of the original patient tumor (A); untreated PDOX tumor (B); PDOX tumor treated with CPA (C); PDOX tumor treated with VPA combined with CAF (D); PDOX tumor treated with Salmonella typhimurium A1-R (E); and PDOX tumor treated with CAF combined with VPA and S. typhimurium A1-R (F). Scale bars: 80 μm.
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