Recombinant human arginase induces apoptosis through oxidative stress and cell cycle arrest in small cell lung cancer

Area of Science:

• Oncology
• Biochemistry
• Cancer Therapeutics

Background:

• Small cell lung cancer (SCLC) has a high relapse rate and lacks specific treatments.
• Arginine deprivation is a potential therapy for tumors auxotrophic for arginine.
• BCT-100, a pegylated arginase, targets arginine auxotrophic tumors.

Purpose of the Study:

• To evaluate the efficacy of BCT-100 in small cell lung cancer (SCLC).
• To identify biomarkers predicting sensitivity to arginase therapy in SCLC.
• To investigate the mechanisms of BCT-100 action in SCLC.

Main Methods:

• Screened 9 SCLC and 1 non-small cell lung carcinoma cell lines for BCT-100 sensitivity.
• Assessed the role of argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC) expression.
• Utilized gene knockdown of OTC in the H841 cell line.
• Evaluated BCT-100 in H446 and H510A xenograft models.

Main Results:

• SCLC cell lines with low ASS1 and OTC expression showed sensitivity to BCT-100.
• Knocking down OTC enhanced BCT-100 sensitivity in H841 cells.
• BCT-100 treatment led to decreased arginine levels, G1 cell cycle arrest, and apoptosis via oxidative stress.
• BCT-100 demonstrated anticancer effects in SCLC xenograft models.

Conclusions:

• BCT-100 is a potential therapeutic agent for SCLC, particularly in tumors with low ASS1/OTC expression.
• ASS1 and OTC expression levels can serve as predictive biomarkers for BCT-100 response.
• Arginine deprivation by BCT-100 induces SCLC cell death through apoptosis and cell cycle arrest.