SYNERGISTIC EFFECTS OF 9-METHOXYCANTHIN-6-ONE WITH CISPLATIN, PACLITAXEL, DOXORUBICIN, AND GEMCITABINE IN SKOV-3 OVARIAN CANCER CELLS

Abstract

Ovarian cancer is one of the most common gynaecological types of cancer among women with a high mortality rate when detected at a late stage. Most of the treatment for late-stage ovarian cancer is via chemotherapy, but it often causes poor prognosis due to toxic side effects. Combination therapy between two or more potent drugs, such as adjuvant therapy is one of the alternative modes of treatment currently being used to reduce the side effects when treating cancer. Natural products still remain an important source for discovering potent anticancer agents, whether they can be used singly or in combination with other treatment(s). Previously, an alkaloid 9-methoxycanthin-6-one (9M) was isolated from Eurycoma longifolia (Tongkat Ali) and had been identified to exert an anti-ovarian cancer effect in vitro and in vivo. However, no studies have been reported on the synergistic effects of 9M when combined with standard chemotherapy drugs in ovarian cancer cells. In this study, the SKOV-3 ovarian cancer cells were treated singly with 9-methoxycanthin-6-one (9M), cisplatin (Cis), paclitaxel (Tax), gemcitabine (Gem) or doxorubicin (Dox). The combined treatments were also performed in which 9M was paired and added with the drug simultaneously (0/0 h), 9M was added first following the drug 4 h later (0/4 h), and the drug was added first following 9M 4 h later (4/0 h) in the 96-well plate. The cells were incubated for 72 h and dead-end assay was conducted using Sulforhodamine B. The results were analysed via Compusyn software V.3.0.1 based on Chou-Talalay method that is based on the median-effect equation which allows quantitative determination of drug interactions in term of Combination Index (CI). CI less than one, equal to one or more than one indicates respectively synergism, additivity or antagonism in combined 9M-drug action. The results showed that 9M exerted synergistic effects when combined with each drug simultaneously (0/0 h) (CI₅₀ ranged from 0.63 to 0.88), with the highest synergism activity when 9M was combined with Tax (CI₅₀ was 0.63). 9M had also shown good synergistic effects when it was added 4 hours later after each drug (CI₅₀ ranged from 0.69 to 0.75) except for Tax (CI₅₀ was 1.24). This study suggests that 9M may have potential to be developed as an anti-ovarian cancer agent and may also be used as adjuvant therapy.