Discovery of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML), a malignant myeloproliferative disease characterized by abnormal activation of BCR-ABL fusion oncoprotein with protein tyrosine kinase (PTK) activity. However, the long-term treatment outcomes with TKIs are strongly limited by multiple drug resistances, resulting in relapse albeit with initial high response rate. Here, we reported a realgar (As 4 S 4 ) nanocrystal-based delivery system to reverse drug resistance for synergistic CML therapy. While As 4 S 4 is extremely insoluble in water, bovine serum albumin (BSA) was rationally screened to effectively stabilize As 4 S 4 nanocrystal with uniformed size of ~40 nm. Imatinib (IMA), a representative TKIs, can be readily loaded into the hydrophobic domain of BSA to develop As 4 S 4 /IMA co-delivery system. Mechanistically, IMA inhibits PTK activity, while As 4 S 4 degrades BCR-ABL1, which co-contribute to tumor suppression via complementary pathways for synergistic effect. Moreover, the nanosystem was modified with folic acid (FA) to enable tumor targetability, which has been demonstrated both in vitro and in vivo, resulting in robust tumor growth inhibition and significantly prolonged mice survival without any noticeable adverse effects. This work designed a synergistic nanoplatform for targeted CML therapy, provided a strategy to address the key limitation of As 4 S 4 for biomedical applications, and highlighted the advantages of the combination between traditional Chinese and western medicine for diseases treatment.
Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin‒proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.
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