Enhancement of the cytotoxic effects of Cytarabine in synergism with Hesperidine and Silibinin in Acute Myeloid Leukemia: An in-vitro approach

Objectives: Acute Myeloid Leukemia (AML) therapy continues to be a daunting challenge. Cytosine Arabinoside (Ara-C) is widely used to treat hematological malignancy in humans, but often becomes ineffective because of increased resistance to the drug which may lead to a worse prognosis. Therefore new strategies are needed to understand the mechanism responsible for drug resistance and to develop new therapies to overcome it. Research evidence based on natural compounds used alone or in combination with current chemotherapeutic agents proved their efficacy to treat and prevent cancer. Hesperidin and Silibinin displayed anti-cancer activity against various types of cancers and cell lines and can be used in combination with Cytarabine with the aim to increase cytotoxicy profile and reduction in drug resistance. Experimental Work: Primary cells obtained from AML patient's bone marrow were used to develop in-vitro model and further exposed to various concentration of Cytarabine (10 nM-5000 nM), Hesperidin (0.5 mu M-100 mu M) and Silibinin (0.5 mu M-100 mu M) alone and in combination with Cytarabine (Hesperidin-25 mu M, Silibinin10 mu M) to check cytotoxicity using MTT assay. Synergistic effect was evaluated by Combination Index method. Result and Conclusion: In-vitro study of Hesperidin and Silibinin indicated their cytotoxicity at IC50 value 50.12 mu M and 16.2 mu M, respectively. Combination Index study revealed Hesperidin and Silibinin both showed synergistic potential and decreased the IC50 value of Cytarabine by similar to 5.9 and similar to 4.5 folds, respectively. Both natural compounds showed potential anti-leukemic activity hence may be used for AML therapy alone or in combination with other chemotherapeutic agents.