Background and Objective: Hepatocellular carcinoma (HCC) is the second
leading cause of cancer death worldwide. Genotoxic stress resistance in patients
often contributes to poor clinical outcomes, and is intensively associated to the upregulation
of Nrf2/ARE signaling pathway. In this study, we examined the connection between the anticancer
activity of two novel indazolo[3,2-b]quinazolinone (IQ) derivatives, IQ-7 and IQ-12,
and their effect on the Nrf2/ARE signaling pathway.
Methods: We initially measured the cytotoxicity of IQ-7 and IQ-12 in Hep3B (human
hepatoma cell) and HL-7702 (normal human liver cell) cell lines, then further detected their
effects on Nrf2/ARE signaling pathway and apoptosis.
Results: IQ-7 and IQ-12 downregulated the expression levels of Nrf2 and its downstream
target genes, such as NQO1, HO-1 and Gclc. In Hep3B cells treated with IQ-7 or IQ-12, the
mitochondrial membrane potential decreased dramatically while the expression level of the
pro-apoptotic protein VDAC1 and anti-apoptotic protein Bcl-2 significantly increased and
decreased, respectively. In addition, IQ-7 (but not IQ-12) also induced the activity of
Caspase-3. Interestingly, IQ-7 appeared to selectively inhibit Hep3B cells while having rare
adverse effect on HL-7702 cells.
Conclusion: The two compounds were shown to induce apoptosis and inhibit the Nrf2/ARE
signaling pathway in Hep3B cells, and IQ-7 was suggested a degree of specificity against
cancer cells. The design of these compounds may therefore represent a new strategy for
designing quinazoline derivatives that could selectively target carcinoma cells.