Thymoquinone chemically conjugated to doxorubicin: antitumor activity and subcellular localization

Doxorubicin is a chemotherapeutic agent that is frequently used in the treatment of several cancers including breast, lung, gastric, ovarian, and thyroid cancers and lymphoma. Despite the wide use of doxorubicin in cancer treatment, the drug has demonstrated severe side effects such as cardiotoxicity, bone marrow aplasia and nephrotoxicity. On the other hand, thymoquinone is a phytochemical antioxidant with known chemopreventive and chemotherapeutic activities. However, thymoquinone suffers from high hydrophobicity, causing poor solubility in aqueous medium, which limits its bioavailability. In this study, we developed a new strategy to attenuate doxorubicin-induced toxicity and improve the bioavailability of thymoquinone by a direct chemical conjugation between doxorubicin and thymoquinone. Strikingly, the generated hybrid drug of thymoquinone-doxorubicin showed a high anti-tumor efficacy, particularly against the MCF-7 breast cancer cells, and low toxicity towards normal human cells. This indicated the potential use of this hybrid drug to target cancer cells with high efficiency and low side toxicity. Moreover, the subcellular localization of the hybrid drug was identified using confocal laser scanning microscopy and fluorescence live-cell imaging, and it was found to be predominantly localized to the endoplasmic reticulum of the cells.