EGFR and HDAC Dual-Target Inhibitor CUDC-101 Enhances the Anti-Myeloma Effects of Bortezomib By Regulating the G2/M Cell Cycle Arrest

Background

Mutiple myeloma (MM) has become the second most prevalent tumor in hematologic diseases, with the age of its onset decreasing year by year. Proteasome inhibitors, immunomodulators and monoclonal antibodies are the most commonly used agents for treating MM. Although the treatment effect and survival time of MM patients has significantly improved with therapies, MM remains an incurable disease, and most MM patients during treatment inevitably undergo primary or secondary drug resistance, leading to disease recurrence and progression, and even death. Therefore, exploring new agents for MM treatment can have significant clinical benefits.

CUDC-101 is a multiple inhibitor that directly blocks the HDAC, EGFR and HER2 signaling pathways. In recent years, many studies have shown that CUDC-101 has strong antitumor effects on many tumor types through inducing caspase-dependent apoptosis, regulating proliferation and migration. In addition, CUDC-101 has been reported to exert a synergistic effect with a lot of conventional drugs, for example, Gemcitabine, Arsenic trioxide, or Carfilzomib. However, it was not reported whether CUDC-101 has an anti-myeloma effect or a synergistic effect when applied with other drugs for MM treatment.

Methods

CCK8 assay was used to detect the inhibitory effect of drugs on the cell proliferation of six human myeloma cell lines. TUNEL assay and Flow cytometry was used to detect the apoptosis and cell cycle. Western bolt was used to detect the expression of apotosis-related proteins and signaling pathway. MM xenografts model was used to indicate the efficacy in vivo.

Results

In this paper, we identified the potential efficacy of CUDC-101 in MM treatment and elaborated the underlying mechanisms. Our results suggest that CUDC-101 can induce cell cycle arrest to significantly inhibit the proliferation of as well as induce cell apoptosis in MM cell lines or primary CD138 positive MM cells through the inhibition of EGFR/PI3K and HDAC signaling pathways. Meanwhile, CUDC-101 also showed marked growth inhibition in the MM xenografts model. In addition, we confirmed the synergistic effect between CUDC-101 and Bortezomib, one of the drugs most commonly used drugs for MM treatment. Using MM cell lines and xenograft models, we demonstrated the remarkable inhibitive effect of these drugs on cell proliferation and tumor growth. Further investigation revealed that the G2/M phase arrest is a pivotal mechanism to achieve this effect, which involves the upregulation of P21 and P27. And these data prove that CUDC-101 is an effective agent in MM therapy.

Conclusion

In summary, we have confirmed the efficacy of CUDC-101 in MM treatment as a single drug or in combination with Bortezomib, and our findings offer a new strategy for MM therapy.

No relevant conflicts of interest to declare.