M₄IDP stimulates ROS elevation through inhibition of mevalonate pathway and pentose phosphate pathway to inhibit...

Area of Science:

• Biochemistry
• Cancer Biology
• Pharmacology

Background:

• Cancer cells rely on redox homeostasis; disrupting it via oxidative stress is a therapeutic strategy.
• M4IDP, a zoledronic acid derivative, induces human colorectal cancer cell death by increasing reactive oxygen species (ROS).
• The precise molecular mechanism of M4IDP's action remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which M4IDP induces oxidative stress and cell death in colorectal cancer cells.
• To investigate the impact of M4IDP on key metabolic pathways, including the pentose phosphate pathway and mevalonate pathway.
• To evaluate the therapeutic potential of M4IDP in preclinical cancer models.

Main Methods:

• In vitro studies using HCT116 cells to assess oxidative stress markers (GSH/GSSG, NADPH/NADP+, MDA).
• Analysis of metabolic pathway flux, enzyme expression (G6PD), and key protein levels (Rap1A, RhoA, CDC42).
• In vivo studies using a human colorectal cancer xenograft mouse model with [18F]FDG uptake assessment.

Main Results:

• M4IDP treatment decreased GSH/GSSG and NADPH/NADP+ ratios and increased MDA levels, indicating oxidative stress.
• M4IDP inhibited pentose phosphate pathway flux, downregulated G6PD expression, and altered levels of Rap1A, RhoA, and CDC42.
• NADPH supplementation, G6PD overexpression, or GGOH supplementation reversed M4IDP-induced ROS and cytotoxicity.
• In vivo, M4IDP inhibited tumor growth and reduced [18F]FDG uptake in xenograft models.

Conclusions:

• M4IDP promotes oxidation in colon cancer cells by inhibiting the mevalonate and pentose phosphate pathways, leading to therapeutic effects.
• This study reveals a novel mechanism for bisphosphonate-induced ROS in malignant cells.
• Findings provide a basis for developing new molecular therapeutic targets and combination therapies involving bisphosphonates for cancer treatment.