Cytotoxicity Activity of Graviola Fruit Extract with Carbamazepine and Valproic Acid Show Antagonistic and Indifferent Effects

OBJECTIVE: Graviola is a tropical fruit with medicinal properties, used for treating various diseases such as inflammation, diabetes, and cancer. Histone deacetylase inhibitors (HDACIs), including carbamazepine (CBZ) and valproic acid (VPA), have been proven strong inhibitors against cancer cell growth. This study investigated the effect of Graviola fruit extract (GFE) on CBZ in healthy rat plasma using high-performance liquid chromatography (HPLC). In addition, the effect of GFE in combination with CBZ and VPA on two human cancer cell lines (PC3 and MCF-7) was explored. METHODS: The CBZ levels were analyzed using a simple validated HPLC method. The linearity was achieved at a 0.9998 coefficient of determination over a range of 75–5000 ng/mL CBZ. The MTT assay was used to quantify the percentage of viable cells. RESULT: The maximum plasma concentration (C(max)) and area under the curve (AUC) for CBZ alone were 4,631 ng/mL and 49,225 ng. h/mL, respectively. However, in the presence of GFE, the values reduced significantly to 2,994 ng/mL and 26,587 ng. h/mL, while the p-value was <0.05. The 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay results for VPA showed a weak cytotoxicity activity on PC3 and MCF-7 cell lines. CONCLUSION: A simple and validated HPLC method was used to determine CBZ levels in rats’ plasma. The plasma CBZ levels (C(max)) were significantly reduced in the presence of GFE, indicating the importance of drug-herb interactions. For in vitro studies, two human cancer cell lines, MCF-7 (breast cancer cells) and PC3 (prostate cancer cells), were used to screen the cytotoxicity activity of GFE, CBZ, and VPA. We observed an antagonism effect for GFE and CBZ combination in both cell lines with FIC values > 4. On the contrary, the combination of GFE and VPA showed an additive or indifferent effect.