Structurally novel steroidal spirooxindole by241 potently inhibits tumor growth mainly through ROS-mediated...

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Cancer cells exhibit elevated reactive oxygen species (ROS) levels, creating a vulnerability to oxidative stress.
• Exploiting the biochemical differences between cancer and normal cells offers a strategy for targeted cancer therapy using ROS-inducing agents.

Purpose of the Study:

• To investigate the anticancer efficacy of a novel steroidal spirooxindole, by241.
• To elucidate the mechanisms underlying by241's selective cancer cell killing properties.

Main Methods:

• In vitro assessment of by241's effects on human cancer cell lines (MGC-803, EC9706) and normal cells.
• Analysis of apoptosis, mitochondrial function, ROS levels, and key protein expression (caspases, mTOR, p53, MDM2, PI3K/AKT, NF-κB).
• In vivo evaluation of by241's toxicity and anticancer efficacy in a MGC-803 xenograft mouse model.

Main Results:

• By241 demonstrated potent, dose-dependent inhibition of cancer cells with minimal toxicity to normal cells.
• By241 induced apoptosis via mitochondrial dysfunction and increased ROS levels, confirmed by N-acetylcysteine (NAC) rescue.
• The compound modulated apoptosis-related proteins, activated caspases-9/-3, inhibited mTOR, activated p53, and affected PI3K/AKT and NF-κB pathways.
• In vivo studies showed good anticancer efficacy and no significant acute oral toxicity.

Conclusions:

• By241 exhibits selective anticancer activity through ROS-mediated apoptosis and modulation of key signaling pathways.
• By241 demonstrates favorable in vivo efficacy and safety, suggesting its potential as a lead compound for cancer therapy development.