Abstract
At present, melanoma is a common malignant tumor with the highest mortality rate of all types of skin cancer. Although the first option for treating melanoma is with chemicals, the effects are unsatisfactory and include poor medication response and high resistance. Therefore, developing new medicines or a novel combination approach would be a significant breakthrough. Here, we present cinnamaldehyde (CA) as a potential candidate, which exerted an antitumor effect in melanoma cell lines. Chemical biology methods of target fishing, molecular imaging, and live cell tracing by an alkynyl–CA probe revealed that the α-enolase (ENO1) protein was the target of CA. The covalent binding of CA with ENO1 changed the stability of the ENO1 protein and affected the glycolytic activity. Furthermore, our results demonstrated that dacarbazine (DTIC) showed a high promoting effect with CA for antimelanoma both in vivo and in vitro. The combination improved the DTIC cell cycle arrest in the S phase and markedly impacted melanoma growth. As a covalent inhibitor of ENO1, CA combined with DTIC may be beneficial in patients with drug resistance in antimelanoma therapy.
Highlights
Melanoma is a highly malignant tumor originating from melanocytes, and its incidence has been rising over the past 20 years, accounting for >80% of skin-cancer-related deaths [1].This disease is characterized by an inconspicuous onset, high malignancy, metastasis, and a poor prognosis [2]
These results certified that both apoptosis and G2/M/S phase arrest triggered by CA contributed to the cytotoxicity in A375 cells
ENO1 reversed the G2/M phase arrest and induced G0/G1 phase arrest in A375 cells (Figure 4D). These results indicated that CA could affect the cell cycle process by inhibiting the function of ENO1, inducing apoptosis in A375 cells
Summary
Melanoma is a highly malignant tumor originating from melanocytes, and its incidence has been rising over the past 20 years, accounting for >80% of skin-cancer-related deaths [1]. Dacarbazine (DTIC), a monofunctional alkylating agent, has been approved as a chemotherapeutic medicine for melanoma treatment [6,7] It exerts antitumor effects via the methylation of nucleic acids or direct DNA damage and leads to a G2/M phase arrest in melanoma cells [8,9]. Previous studies have demonstrated that TMZ can enhance the antitumor activity of FTM, but they have limited effectiveness [12,13,14]. We found that CA could produce promoting effects with DTIC, and it significantly improved the therapeutic efficacy both in vitro and in vivo These results may provide a new potential strategy for the treatment of melanoma
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