ROS and RNS induced apoptosis through p53 and iNOS mediated pathway by a dibasic hydroxamic acid molecule in leukemia...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Anticancer drugs often cause toxicity to normal cells, necessitating the development of agents with selective toxicity.
• Hydroxamic acids are known to suppress tumor cell growth via apoptosis, but their mechanisms are not fully understood.

Purpose of the Study:

• To investigate the apoptotic potential of oxayl bis (N-phenyl) hydroxamic acid (OBPHA), a dibasic hydroxamic acid derivative.
• To elucidate the mechanism of action of OBPHA, including its role in reactive oxygen and nitrogen species generation and its effect on drug-resistant cancer cells.

Main Methods:

• Synthesis and structural determination (crystal structure) of OBPHA.
• Assessment of OBPHA's ability to induce apoptosis in doxorubicin-resistant T-lymphoblastic leukemia cells (CEM/ADR5000).
• Analysis of reactive oxygen species (ROS), nitric oxide (NO), and glutathione (GSH) levels, as well as caspase 3 activation, p53 signaling, and HDAC3 expression.

Main Results:

• OBPHA selectively induces apoptosis in cancerous cells, irrespective of their drug-resistant phenotype.
• Apoptosis induction by OBPHA is mediated by the generation of ROS and NO, possibly through auto-degeneration of the hydroxamic acid groups.
• OBPHA activates caspase 3-mediated intrinsic apoptosis and a p53-dependent signaling cascade, while downregulating HDAC3 expression.

Conclusions:

• OBPHA demonstrates significant anticancer potential by selectively triggering apoptosis through ROS and NO generation.
• The study provides structural insights into apoptosis induction by hydroxamic acid derivatives.
• OBPHA serves as a valuable lead compound for developing novel ROS and RNS-generating chemicals for p53-dependent cancer therapy.