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Super Methotrexate-resistant Osteosarcoma Cells Retain Their Sensitivity to Recombinant Methioninase: Targeting

Yusuke Aoki1,2,3, Qinghong Han4,2, Yutaro Kubota4,2

  • 1AntiCancer Inc, San Diego, CA, U.S.A.; yaoki0630@gmail.com.

Anticancer Research
|March 4, 2025
PubMed
Abstract

Insights

Methionine restriction using recombinant methioninase (rMETase) effectively treated super methotrexate (MTX)-resistant osteosarcoma cells. This approach shows promise for overcoming drug resistance in osteosarcoma patients.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Osteosarcoma drug resistance poses a significant clinical challenge.
  • Methotrexate (MTX)-resistant osteosarcoma cells (143B-MTXSR) exhibit 5,500-fold resistance due to dihydrofolate reductase (DHFR) overexpression.
  • Previous studies established 143B-MTXSR cells from parental 143B-P cells.

Purpose of the Study:

  • To investigate the therapeutic potential of methionine restriction via recombinant methioninase (rMETase) against MTX-resistant osteosarcoma.
  • To determine if rMETase can overcome the extreme drug resistance observed in 143B-MTXSR cells.

Main Methods:

  • Utilized previously established 143B-MTXSR cells.
  • Assessed sensitivity to methionine restriction by rMETase using the WST-8 assay.
  • Compared the efficacy of rMETase between 143B-MTXSR and parental 143B-P cells.

Main Results:

  • 143B-MTXSR cells demonstrated high sensitivity to rMETase-induced methionine restriction.
  • The IC50 values for rMETase were similar for both resistant (0.38 U/ml) and parental (0.36 U/ml) cells.
  • rMETase effectively overcame the 5,500-fold MTX resistance.

Conclusions:

  • Methionine restriction mediated by rMETase is a viable strategy to combat MTX-resistant osteosarcoma.
  • rMETase shows potential as a clinical approach for treating drug-resistant osteosarcoma.
  • This study highlights a novel therapeutic avenue for recalcitrant osteosarcoma cases.
Keywords:
Hoffman EffectOsteosarcomamethionine addictionmethionine restrictionmethotrexaterMETaserecombinant methioninaseresistance

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