Thymoquinone and chemoresistance in non-small cell lung cancer: Preclinical promise or therapeutic potential?

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and remains a major cause of cancer-related mortality worldwide.Despite advances in targeted therapies and immunotherapies, resistance to platinum-based chemotherapy, particularly cisplatin continues to undermine treatment success [1].The quest for agents capable of modulating chemoresistance has drawn increasing attention to phytochemicals, among which thymoquinone (TQ), the principal bioactive component of Nigella sativa L. (black cumin), has demonstrated notable antitumor properties in preclinical research [2].Emerging evidence suggests that TQ exhibits cytotoxic effects against various NSCLC cell lines, including A549 and H460, primarily through the induction of apoptosis, suppression of proliferation, and inhibition of metastatic potential [3][4][5].Notably, Jafri et al. demonstrated that TQ synergistically enhanced the effects of cisplatin in H460 xenograft models, leading to significant tumor growth inhibition compared to either agent alone [6].More recently, Gurbilek et al. reported that TQ sensitized H460 cells to both cisplatin and ionizing radiation by modulating PPAR- and NF-B signaling, two pathways implicated in chemoresistance and inflammation-driven tumor progression [5].Beyond its interaction with cisplatin, TQ has shown promise in targeting molecular pathways associated with therapy resistance.For instance, Gomathinayagam et al. discussed how TQ targets multiple oncogenic signaling pathways such as PI3K/Akt/mTOR, STAT3, and Bcl-2 which are implicated in promoting cell survival, proliferation, and resistance to chemotherapy in various cancer models [7].In another recent study, Zhang et al. observed that TQ disrupted cancer stem cell (CSC) characteristics by promoting YAP degradation, thereby impeding selfrenewal and tumorigenic potential [8].Given that CSCs play a pivotal role in recurrence and resistance, these findings highlight a plausible mechanism by which TQ may mitigate therapeutic failure [8].