Dispiro-indanedione hybrid of parthenin induces p53-independent apoptosis and suppresses tumor progression in colorectal cancer models

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, with mutation of the p53 gene found in up to 80% of advanced CRC cases, resulting in apoptotic halt and significant drug resistance. The development of new drugs targeting the mutated p53 gene in CRC patients is limited. This study explored the anticancer potential of a dispiro-indanedione hybrid of parthenin (DIHP) in a p53-independent manner using HCT 116 (human colorectal carcinoma cell line). DIHP induced apoptosis by blocking JAK2-STAT3-dependent survival protein like Bcl-xL, in cooperation with TRAIL (Apo2L), leading to dose-dependent cell death and cell cycle arrest. Acute toxicity and pharmacokinetic (PK) studies revealed DIHP is significantly less toxic than its parent parthenin and exhibits a favorable PK profile respectively. Efficacy assessments in both HCT 116 xenograft and AOM (Azoxymethane)/DSS (Dextran Sulfate Sodium) induced colitis-associated colorectal cancer (CAC) mouse models demonstrated significant tumor growth suppression and improved survival. Mechanistically, DIHP downregulated key oncogenic survival pathways including PI3K/AKT, NF-κB, STAT3, and ERK. Additionally, DIHP attenuated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in the CAC model. These findings highlight the potential of DIHP in combating CRC, providing a new opportunity for the development of anticancer treatment with improved efficacy and possible therapeutic benefits.