Olsalazine pretreatment augments chemosensitivity of gemcitabine in hepatocellular carcinoma

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Olsalazine, a DNA hypomethylating agent, previously inhibited breast cancer cell growth.
• Hepatocellular carcinoma (HCC) remains a significant global health challenge with limited effective therapies.
• Gemcitabine is a standard chemotherapeutic agent, but its efficacy in HCC can be limited.

Purpose of the Study:

• To evaluate the efficacy of olsalazine pretreatment in potentiating gemcitabine chemosensitivity for HCC treatment.
• To investigate the molecular interactions and biological effects of the combination therapy.
• To assess the impact on tumor progression, liver function, and inflammatory markers.

Main Methods:

• In silico molecular docking of olsalazine with DNMT1 and gemcitabine with DNA.
• In vitro cytotoxicity assays (MTT) on human HePG2 cells.
• In vivo studies using a chemically induced HCC animal model.
• Assessment of serum biochemistry, inflammatory cytokines (TNF-α, IL-6), CRP, LDH, P53, and oxidative stress markers.
• Histopathology and immunohistochemistry (IHC) for morphological changes and P53 expression.

Main Results:

• Molecular docking showed favorable binding energies for olsalazine-DNMT1 and gemcitabine-DNA interactions.
• Olsalazine pretreatment significantly enhanced gemcitabine's antiproliferative effects in cell lines and animal models.
• The combination therapy led to reduced liver weight, improved survival rates, and normalized liver function markers.
• Significant reduction in inflammatory markers (CRP, LDH, TNF-α, IL-6) and oxidative stress was observed.
• Histopathology and IHC confirmed improved liver morphology and enhanced P53 expression.

Conclusions:

• Sequential combination of olsalazine and gemcitabine demonstrates significant therapeutic potential for HCC.
• Olsalazine pretreatment enhances gemcitabine efficacy by modulating molecular targets and reducing tumor-promoting inflammation.
• This combination strategy offers a promising approach to improve treatment outcomes in hepatocellular carcinoma progression.