Enhancing thymoquinone’s anticancer potential by combinatorial, conjugational and nanoformulation approaches -

Abstract

Thymoquinone (TQ), is the major bioactive component of Nigella sativa black seed oil. Our laboratory has long been investigating TQ’s anticancer potential as well as its mechanism of action in both solid and non-solid tumors. Our results show that TQ modulates signaling pathways that are key to cancer progression, inhibits cancer cell viability in all cancer cell lines tested, while sparing the normal cells. The development of TQ however, is hindered by several factors including its hydrophobicity and limited bioavailability, its binding to non-specific targets which abrogate its activity and by the resistance of specific cell lines to treatment with TQ. In this project, we attempted to enhance TQ’s anticancer activity by using combinatorial, conjugation and nanoparticle approaches. Multi-drug regimens are commonly recommended for overcoming chemoresistance of cancer cells to a specific drug. Furthermore, combination treatment can potentially inhibit cancer viability without using high drug doses which cause severe toxic side effects. Doxorubicin (Dox) is a clinically approved drug for the treatment of a wide range of cancers including leukemia and lymphomas. However, high doses of the Dox have been associated with cardiotoxicity. To this aim, TQ was tested in combination with low doses of Dox in an adult T-cell leukemia (ATL) model. ATL is an aggressive malignancy of mature activated CD4+ T-cells infected with the human T-cell lymphotropic virus type I (HTLV-1). We evaluated the effects of TQ and Dox combination treatment on cell death and cell cycle of HTLV-1 positive and negative cancer cells using MTT, trypan blue and propidium iodide (PI). Our data shows resistance of the HTLV-1 positive cancer cell line to treatment with Dox. However, co-treatment with TQ and Dox triggers cell death in both HTLV-1 positive and negative cancer cell lines. Specifically, the combination enables the use of low Dox concentrations to achieve the same viability inhibition effects as those observed in cells treated wi