Thymoquinone upregulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells

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Chemotherapeutic resistance and cancer recalcitrance are major hindrances resulting in poor treatment outcome. Targeting cell survival pathway with naturally occurring compounds has begun to receive much attention in cancer research. Thymoquinone (TQ) is a bioactive constituent of the volatile oil derived from seeds of the medicinal plant Nigella sativa Linn. TQ has shown promising anticarcinogenic and antitumor activities through different mechanisms. However, the effect of TQ on cell signaling and survival pathways in resistant cells has not been fully delineated. Here, we report that TQ exhibited antiproliferative effect, induced apoptosis, disrupted mitochondrial membrane potential and triggered the activation of caspases and PARP-1 cleavage in doxorubicin-resistant human breast cancer cells. Flow cytometric analysis showed sub-G1 peak of apoptotic population and cell cycle arrest at G2/M phase following TQ treatment. TQ treatment of doxorubicin-resistant cells modulated Akt phosphorylation, PTEN expression, and Bax/Bcl2 ratios. Taken together, our data indicate that the antiproliferative effect of TQ in doxorubicin-resistant human breast cancer cells is associated with apoptosis, upregulation of PTEN, inhibition of Akt pathway and G2/M arrest. As the loss of PTEN function and Akt activation are often observed in a variety of cancers and drug resistance respectively, our data strongly suggest the potential clinical usefulness of TQ for the treatment of those conditions. This work was supported by NIH grants CA93413, ES6074 and ES12991 to A. A. W.