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

Article

Author: Han, Qinghong ; Igarashi, Kentaro ; KANG, BYUNG MO ; MORINAGA, SEI ; TSUCHIYA, HIROYUKI ; YAMAMOTO, NORIO ; HAYASHI, KATSUHIRO ; Kang, Byung Mo ; IGARASHI, KENTARO ; DEMURA, SATORU ; HOFFMAN, ROBERT M. ; BOUVET, MICHAEL ; MIWA, SHINJI ; HAN, QINGHONG ; MIZUTA, KOHEI ; Hayashi, Katsuhiro ; Morinaga, Sei ; Higuchi, Takashi ; HIGUCHI, TAKASHI ; SATO, MOTOKAZU ; Tsuchiya, Hiroyuki ; KIMURA, HIROAKI ; Bouvet, Michael ; Hoffman, Robert M ; Kimura, Hiroaki ; Yamamoto, Norio ; Mizuta, Kohei ; Miwa, Shinji ; Sato, Motokazu ; Demura, Satoru

BACKGROUND/AIMMethionine 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-2^Tet-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 METHODSMiaPaCa-2^Tet-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-2^Tet-On 53BP1-GFP pancreatic cancer cells were determined. Cell viability and DDR with rMETase alone, paclitaxel alone, and their combination were measured in MiaPaCa-2^Tet-On 53BP1-GFP cells.RESULTSThe IC₂₅ of rMETase on MiaPaCa-2^Tet-On 53BP1-GFP cells was 1.66 U/ml. The IC₂₅ for paclitaxel on MiaPaCa-2^Tet-On 53BP1-GFP cells was 3.31 nM. The combination of rMETase and paclitaxel synergistically reduced the viability of MiaPaCa-2^Tet-On 53BP1-GFP cells. The IC₅₀ of paclitacel on MiaPaCa-2^Tet-On 53BP1-GFP cells was 5.1 nM. The IC₅₀ of rMETase on MiaPaCa-2^Tet-On 53BP1-GFP cells was 2.3 U/ml. The combination of rMETase (IC₅₀) plus paclitaxel (IC₅₀) on MiaPaCa-2^Tet-On 53BP1-GFP cells also caused more DNA damage than either agent alone.CONCLUSIONThe present study suggests the synergy of methionine restriction and chemotherapy is due, at least in part, to DNA damage of cancer cells.

01 Nov 2024·Anticancer Research

Recombinant Methioninase Synergistically Reverses High-docetaxel Resistance Developed in Osteosarcoma Cells

Article

Author: Han, Qinghong ; Hayashi, Katsuhiro ; Tsuchiya, Hiroyuki ; Morinaga, Sei ; Kimura, Hiroaki ; Kang, Byung M ; Igarashi, Kentaro ; Higuchi, Takashi ; Hoffman, Robert M ; Bouvet, Michael ; Mizuta, Kohei ; Miwa, Shinji ; Yamamoto, Norio ; Demura, Satoru

BACKGROUND/AIMDocetaxel combined with gemcitabine is a second-line therapy for osteosarcoma, but its efficacy is limited by the development of docetaxel resistance. The aim of the present study was to determine whether recombinant methioninase (rMETase) could reverse docetaxel resistance developed in osteosarcoma cells.MATERIALS AND METHODSDocetaxel-resistant 143B (DTR-143B) osteosarcoma cells were established by treating the parental 143B cells to increasing docetaxel concentrations (0.14-24 nM) over 5 months. The 50% inhibitory concentration (IC₅₀) of docetaxel and rMETase as well as their combination on human osteosarcoma cells 143B and DTR-143B were determined. Four groups were analysed in vitro: untreated control; docetaxel; rMETase; docetaxel plus rMETase.RESULTSThe IC₅₀ value of docetaxel for DTR-143B cells was 31.1 nM, compared to 4.38 nM for the parental 143B cells, a 7-fold increase. The combination of rMETase (0.53 U/ml) and docetaxel (4.38 nM) sensitized DTR-143B cells to docetaxel resulting in an inhibition of 73.7% compared to docetaxel alone (7.3%) or rMETase alone (54.6%) (p<0.05). rMETase thus increased the efficacy of docetaxel 10-fold on docetaxel-resistant osteosarcoma cells.CONCLUSIONrMETase reversed docetaxel resistance of DTR-143B in vitro. The present results indicate the clinical potential of rMETase to overcome docetaxel resistance in osteosarcoma patients.

01 Sep 2024·Anticancer Research

Overcoming High Trabectedin Resistance of Soft-tissue Sarcoma With Recombinant Methioninase: A Potential Solution of a Recalcitrant Clinical Problem

Article

Author: Han, Qinghong ; Igarashi, Kentaro ; Hayashi, Katsuhiro ; Morinaga, Sei ; Higuchi, Takashi ; Kang, Byung M ; Tsuchiya, Hiroyuki ; Bouvet, Michael ; Hoffman, Robert M ; Kimura, Hiroaki ; Yamamoto, Norio ; Mizuta, Kohei ; Miwa, Shinji ; Sato, Motokazu ; Demura, Satoru

BACKGROUND/AIMDrug resistance has been a recalcitrant problem for sarcoma patients for many decades. Trabectedin is a second-line chemotherapy for soft-tissue sarcoma that often leads to resistance and death of the patients. The objective of the present study was to address the issue of trabectedin-chemoresistance in HT1080 fibrosarcoma cells by combining recombinant methioninase (rMETase) with trabectedin and examining their efficacy on trabectedin-resistant fibrosarcoma cells in vitro.MATERIALS AND METHODSTrabectedin-resistant HT1080 (TR-HT1080) cells were generated by subjecting HT1080 human fibrosarcoma cells to increasing trabectedin concentrations (3.3-8 nM). IC₅₀ values for trabectedin and rMETase were compared for HT1080 and TR-HT1080 cells. TR-HT 1080 cells were placed into four groups to determine synergy of rMETase and trabectedin on TR-HT1080 cells: a control group with no treatment; a group treated with trabectedin (3.3 nM); a group treated with rMETase (0.75 U/ml); and a group treated with both trabectedin (3.3 nM) and rMETase (0.75 U/ml).RESULTSThe IC₅₀ value of trabectedin- on TR-HT1080 cells was 42.9 nM, whereas the IC₅₀ value of trabectedin on the parental HT1080 cells was 3.3 nM, indicating a 13-fold increase. The combination of rMETase (0.75 U/ml) and trabectedin (3.3 nM) was synergistic on TR-HT1080 cells resulting in an inhibition of 64.2% compared to trabectedin alone (5.7%) or rMETase alone (50.5%) (p<0.05). rMETase increased the efficacy of trabectedin 11-fold on trabectedin-resistant fibrosarcoma cells.CONCLUSIONThe combined administration of trabectedin and rMETase was synergistic on the viability of TR-HT1080 cells in vitro. The combination of rMETase and trabectedin has promising clinical potential for overcoming chemo-resistance of soft-tissue sarcoma.

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