Enhancement of chemotherapeutic agent-induced apoptosis by inhibition of NF-κB using ursolic acid

NF-kappa B activation is known to reduce the efficiency of chemotherapy in cancer treatment. Ursolic acid, a minimally toxic compound, has shown the capability to inhibit NF-kappa B activation in living cells. Here, for the first time, we investigated the effects and mechanisms of NF-kappa B inhibition by ursolic acid on chemotherapy treatment (Taxol or cisplatin) of cancer. ASTC-a-1 (human lung adenocarcinoma), He la (human cervical cancer) cells, primary normal mouse cells of lung and liver and mouse in vivo model were used. Activity of signal factors (NF-kappa B, Akt, Fas/FasL, BID, Bcl-2, cytochrome c and caspase-8, 3) was used to analyze the mechanisms of ursolic acid-chemo treatment. Ursolic acid-mediated suppression of NF-kappa B drastically reduced the required dosage of the chemotherapeutic agents to achieve identical biological endpoints and enhanced the chemotherapeutic agent-induced cancer cells apoptosis. Chemosensitization by ursolic acid in cancer cells was dependent on the amplified activation of intrinsic pathway (caspase-8-BID-mitochondria-cytochrome c-caspase-3) by augmentation of BID cleavage and activation of Fas/FasL-caspase-8 pathway. Prolonged treatment with relatively low doses of ursolic acid also sensitized cancer cells to the chemotherapeutic agents through suppression of NF-kappa B. Chemosensitization by ursolic acid was observed only in cancer cells, but not in primary normal cells. The inhibitive effect of ursolic acid on NF-kappa B was reversible, and the reversal was not accompanied by a loss in cells viability. By supplementing chemotherapy with minimally toxic ursolic acid, it is possible to improve the efficacy of cancer treatment by significantly reducing the necessary drug dose without sacrificing the treatment results.