Abstract
BackgroundDCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown.MethodsWe generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models.ResultsDCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G2/M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933.ConclusionsOur study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.
Highlights
Multiple Myeloma (MM) is a malignant hematologic disease characterized by clonal proliferation of malignant plasma cells
We have previously reported that it exhibits strong anti-cancer activity in MM13, diffuse large B-cell lymphoma (DLBCL) [13] and T-cell leukemia/lymphoma [14]
Our results showed that DCZ3301 treatment activated the ATMATR-checkpoint kinase 1 (CHK1) signaling pathway and restored the sensitivity of BTZ-resistant cells
Summary
Multiple Myeloma (MM) is a malignant hematologic disease characterized by clonal proliferation of malignant plasma cells. Over the past decade, there has been an increase in the cases of drugresistance and MM relapse following BTZ treatment [3]. Once a patient develops resistance, BTZ is rendered ineffective at the usual tolerable doses [4]. Since the safety margin of BTZ is very narrow, increasing its dose will significantly augment the risk of side effects. There is an urgent need to develop new therapeutic compounds to counter BTZ resistance in MM. DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma.
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