PT  - JOURNAL ARTICLE
AU  - MORINAGA, SEI
AU  - HAN, QINGHONG
AU  - MIZUTA, KOHEI
AU  - KANG, BYUNG MO
AU  - SATO, MOTOKAZU
AU  - BOUVET, MICHAEL
AU  - YAMAMOTO, NORIO
AU  - HAYASHI, KATSUHIRO
AU  - KIMURA, HIROAKI
AU  - MIWA, SHINJI
AU  - IGARASHI, KENTARO
AU  - HIGUCHI, TAKASHI
AU  - TSUCHIYA, HIROYUKI
AU  - DEMURA, SATORU
AU  - HOFFMAN, ROBERT M.
TI  - Extensive DNA Damage and Loss of Cell Viability Occur Synergistically With the Combination of Recombinant Methioninase and Paclitaxel on Pancreatic Cancer Cells which Report DNA-Damage Response in Real Time
AID  - 10.21873/cgp.20475
DP  - 2024 Nov 01
TA  - Cancer Genomics - Proteomics
PG  - 585--590
VI  - 21
IP  - 6
4099  - http://cgp.iiarjournals.org/content/21/6/585.short
4100  - http://cgp.iiarjournals.org/content/21/6/585.full
SO  - Cancer Genomics Proteomics2024 Nov 01; 21
AB  - Background/Aim: Methionine restriction selectively arrests cancer cells during the S-phase of the cell cycle. We hypothesized that DNA damage may occur in S-phase in cancer cells during methionine restriction. To determine if this occurs, we used MiaPaCa-2Tet-On 53BP1-green fluorescent protein (GFP) pancreatic cancer cells, which report GFP fluorescence in real time after DNA-damage response (DDR) in these cells. We also determined whether a chemotherapy drug in combination with methionine restriction increases the rate of DNA damage. Materials and Methods: MiaPaCa-2Tet-On 53BP1-GFP cells were used for in vitro experiments. The 25% and 50% inhibitory concentrations (IC25 and IC50, respectively) of recombinant methioninase (rMETase) and paclitaxel on MiaPaCa-2Tet-On 53BP1-GFP pancreatic cancer cells were determined. Cell viability and DDR with rMETase alone, paclitaxel alone, and their combination were measured in MiaPaCa-2Tet-On 53BP1-GFP cells. Results: The IC25 of rMETase on MiaPaCa-2Tet-On 53BP1-GFP cells was 1.66 U/ml. The IC25 for paclitaxel on MiaPaCa-2Tet-On 53BP1-GFP cells was 3.31 nM. The combination of rMETase and paclitaxel synergistically reduced the viability of MiaPaCa-2Tet-On 53BP1-GFP cells. The IC50 of paclitacel on MiaPaCa-2Tet-On 53BP1-GFP cells was 5.1 nM. The IC50 of rMETase on MiaPaCa-2Tet-On 53BP1-GFP cells was 2.3 U/ml. The combination of rMETase (IC50) plus paclitaxel (IC50) on MiaPaCa-2Tet-On 53BP1-GFP cells also caused more DNA damage than either agent alone. Conclusion: The present study suggests the synergy of methionine restriction and chemotherapy is due, at least in part, to DNA damage of cancer cells.