NAD (P)H Quinone Dehydrogenase 1-Targeting Triptolide Analogue Causes Tumor Regression and Sensitizes Cisplatin-Resistant Lung Cancer to Chemotherapy.

Cisplatin (DDP) is a first-line chemotherapeutic drug against lung cancer. Nonetheless, the effectiveness of this drug is hampered by drug resistance. Overcoming drug resistance is crucial for improving the outcomes of lung cancer treatment. Here, we reported the effect of CX-23, an activated triptolide analogue that targets NAD (P)H quinone dehydrogenase 1 (NQO1), on DDP-resistant lung cancer and sensitizes DDP-resistant lung cancer to chemotherapy. Our findings unveiled the antiproliferative activity of CX-23 against both A549- and DDP-resistant A549 (A549/DDP) cells while enhancing the chemosensitivity of these cells to DDP. Notably, CX-23 demonstrated no toxicity toward normal lung cells. Further investigations revealed that CX-23 exerts its effects by blocking AKT phosphorylation, leading to reduced expression of Mcl-1 and Bcl-2, and upregulating cleaved-caspase-3 levels, ultimately inducing apoptosis in cancer cells. CX-23 can be rapidly transformed in both A549 and A549/DDP cell lysates while remaining stable in mouse plasma and normal lung tissues. Pharmacokinetic analysis showed that CX-23 can distribute to lung tissues. Moreover, in vivo studies showed that CX-23 can prevent DDP-resistant lung cancer progression without causing any toxicity in the liver, kidneys, or lungs after 6 weeks of treatment. The combination of CX-23 and DDP not only significantly inhibited tumor progression compared to DDP alone but also attenuated DDP-induced kidney toxicity. These findings suggest that CX-23 alone or in combination with DDP may provide an alternative therapeutic option for DDP-resistant lung cancer.