PANapoptosis Elicited by Advanced Bismuth-Based Anticancer Drugs through Oxidative Damage

Area of Science:

• Biochemistry
• Pharmacology
• Materials Science

Background:

• Tetramethylpyrazine (TMP) exhibits anticancer properties but suffers from poor solubility and bioavailability.
• Developing novel drug delivery systems is crucial for improving TMP's clinical efficacy.

Purpose of the Study:

• To synthesize and evaluate a bismuth-based metal complex (TMP-Bi) of Tetramethylpyrazine.
• To investigate the anticancer mechanisms and therapeutic potential of TMP-Bi in vitro and in vivo.

Main Methods:

• Formation of the TMP-Bi complex by combining TMP with bismuth.
• In vitro and in vivo anticancer efficacy studies.
• Analysis of reactive oxygen species generation, mitochondrial damage, apoptosis, and pyroptosis pathways (GSDMD cleavage, caspase-1, NF-κB).
• Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.

Main Results:

• TMP-Bi significantly enhanced anticancer activity compared to TMP alone.
• TMP-Bi induced PANoptosis in cancer cells, characterized by increased reactive oxygen species, mitochondrial damage, and apoptosis.
• Activation of the pyroptosis pathway, upregulation of caspase-1 and NF-κB, and increased lactate dehydrogenase release were observed.
• KEGG analysis indicated affected pathways including calcium signaling, TNF response, inflammatory response, and apoptosis.

Conclusions:

• TMP-Bi demonstrates superior anticancer effects by orchestrating multiple cell death pathways, including PANoptosis and apoptosis.
• The low toxicity and biocompatibility of bismuth enhance the therapeutic profile of TMP-Bi.
• TMP-Bi represents a promising novel therapeutic agent for cancer treatment due to its enhanced efficacy and favorable safety profile.