Abstract
Management of neuroblastoma is challenging because of poor response to drugs, chemotherapy resistance, high relapse, and treatment failures. Doxorubicin is a potent anticancer drug commonly used for neuroblastoma treatment. However, doxorubicin induces considerable toxicities, particularly those caused by oxidative-related damage. To minimize drug-induced adverse effects, the combined use of anticancer drugs with natural-derived compounds possessing antioxidant properties has become an interesting treatment strategy. Barakol is a major compound found in Cassia siamea, an edible plant with antioxidant and anticancer properties. Therefore, barakol could potentially be used in combination with doxorubicin to synergize the anticancer effect, while minimizing the oxidative-related toxicities. Herein, the potential of barakol (0.0043-43.0 μM) to synergize the anticancer effect of low-dose doxorubicin (0.5 and 1.0 μM) was investigated. Results indicated that barakol could enhance the cytotoxic effect of low-dose doxorubicin by affecting the cell viability of the treated cells. Furthermore, the co-treatment with barakol and low-dose doxorubicin decreased the levels of intracellular ROS when compared with the control. Moreover, the antimetastatic effect of the barakol itself was studied through its ability to inhibit metalloproteinase-3 (MMP-3) activity and prevent cell migration. Results revealed that the barakol inhibited MMP-3 activity and prevented cell migration in time- and dose-dependent manners. Additionally, barakol was a non-cytotoxic agent against the normal tested cell line (MRC-5), which suggested its selectivity and safety. Taken together, barakol could be a promising compound to be further developed for combination treatment with low-dose doxorubicin to improve therapeutic effectiveness but decrease drug-induced toxicities. The inhibitory effects of barakol on MMP-3 activity and cancer cell migration also supported its potential to be developed as an antimetastatic agent.