Cytochrome P450 1A2 overcomes nuclear factor kappa B-mediated sorafenib resistance in hepatocellular carcinoma

Area of Science:

• Hepatocellular Carcinoma Research
• Molecular Oncology
• Drug Resistance Mechanisms

Background:

• Sorafenib resistance is a major challenge in treating advanced hepatocellular carcinoma (HCC).
• Nuclear factor kappa B (NF-κB) activation contributes to sorafenib resistance.
• Cytochrome P450 1A2 (CYP1A2) acts as a tumor suppressor in HCC and its expression is inversely related to NF-κB.

Purpose of the Study:

• To investigate if CYP1A2 can overcome sorafenib resistance in HCC.
• To determine the roles of CYP1A2 and NF-κB p65 in sorafenib desensitization.

Main Methods:

• Establishment of sorafenib-resistant (SR) HCC cell lines.
• Analysis of CYP1A2 and NF-κB p65 expression in SR cells.
• Experimental manipulation of CYP1A2 and NF-κB p65 levels (overexpression/silencing).
• In vitro and in vivo assessment of cell proliferation, sensitivity, and tumor growth.
• Combination therapy studies with sorafenib and omeprazole (a CYP1A2 inducer).

Main Results:

• SR cells exhibited decreased CYP1A2 and increased NF-κB p65.
• CYP1A2 overexpression reduced SR cell proliferation, enhanced sorafenib sensitivity, and inhibited NF-κB.
• CYP1A2 silencing had opposite effects.
• Combination of sorafenib and omeprazole inhibited SR cell growth and tumor progression in vitro and in vivo.
• This combination therapy increased CYP1A2 expression and suppressed NF-κB signaling.
• NF-κB p65 overexpression promoted SR cell growth and sorafenib resistance, which was reversed by CYP1A2 overexpression.
• HCC tissues showed reduced CYP1A2 and elevated NF-κB p65.

Conclusions:

• CYP1A2 sensitizes sorafenib-resistant HCC cells by inhibiting the NF-κB p65 pathway.
• Omeprazole combined with sorafenib demonstrates synergistic effects in overcoming acquired sorafenib resistance in HCC.