Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

Shuuya Yano, Kiyoto Takehara, Ming Zhao, Yuying Tan, Qinghong Han, Shukuan Li, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G1 phase. Longitudinal real-time FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G2/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G0/G1 to S/G2/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G2, shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G2 phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of “decoy, trap and shoot” chemotherapy.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalCell Cycle
DOIs
Publication statusAccepted/In press - Jun 7 2016

Fingerprint

Ubiquitination
Salmonella typhimurium
Cell Cycle
Fluorescence
Neoplasms
L-methionine gamma-lyase
Drug Therapy
Cell Cycle Resting Phase
Hair Follicle
G2 Phase
Poisons
Cytotoxins
G1 Phase
Paclitaxel

Keywords

  • cancer
  • cell-cycle
  • cisplatinum
  • decoy
  • FUCCI
  • methioninase
  • nude mice
  • paclitaxel
  • Salmonella typhimurium A1-R
  • stomach cancer
  • trap

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging. / Yano, Shuuya; Takehara, Kiyoto; Zhao, Ming; Tan, Yuying; Han, Qinghong; Li, Shukuan; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

In: Cell Cycle, 07.06.2016, p. 1-9.

Research output: Contribution to journalArticle

@article{d8eac1bb026f4868b8a3e8c73576fdf3,
title = "Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging",
abstract = "We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI). Approximately 90{\%} of cancer cells in the center and 80{\%} of total cells of an established tumor are in G0/G1 phase. Longitudinal real-time FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G2/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G0/G1 to S/G2/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G2, shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G2 phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of “decoy, trap and shoot” chemotherapy.",
keywords = "cancer, cell-cycle, cisplatinum, decoy, FUCCI, methioninase, nude mice, paclitaxel, Salmonella typhimurium A1-R, stomach cancer, trap",
author = "Shuuya Yano and Kiyoto Takehara and Ming Zhao and Yuying Tan and Qinghong Han and Shukuan Li and Michael Bouvet and Toshiyoshi Fujiwara and Hoffman, {Robert M.}",
year = "2016",
month = "6",
day = "7",
doi = "10.1080/15384101.2016.1181240",
language = "English",
pages = "1--9",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",

}

TY - JOUR

T1 - Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

AU - Yano, Shuuya

AU - Takehara, Kiyoto

AU - Zhao, Ming

AU - Tan, Yuying

AU - Han, Qinghong

AU - Li, Shukuan

AU - Bouvet, Michael

AU - Fujiwara, Toshiyoshi

AU - Hoffman, Robert M.

PY - 2016/6/7

Y1 - 2016/6/7

N2 - We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G1 phase. Longitudinal real-time FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G2/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G0/G1 to S/G2/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G2, shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G2 phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of “decoy, trap and shoot” chemotherapy.

AB - We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G1 phase. Longitudinal real-time FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G2/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G0/G1 to S/G2/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G2, shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G2 phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of “decoy, trap and shoot” chemotherapy.

KW - cancer

KW - cell-cycle

KW - cisplatinum

KW - decoy

KW - FUCCI

KW - methioninase

KW - nude mice

KW - paclitaxel

KW - Salmonella typhimurium A1-R

KW - stomach cancer

KW - trap

UR - http://www.scopus.com/inward/record.url?scp=84974719990&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84974719990&partnerID=8YFLogxK

U2 - 10.1080/15384101.2016.1181240

DO - 10.1080/15384101.2016.1181240

M3 - Article

C2 - 27152859

AN - SCOPUS:84974719990

SP - 1

EP - 9

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

ER -