Cinnamaldehyde Enhances Antimelanoma Activity through Covalently Binding ENO1 and Exhibits a Promoting Effect with Dacarbazine

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.

Alpha-Enolase (ENO1) Correlates with Invasiveness of Cutaneous Melanoma—An In Vitro and a Clinical Study

“…There is an increasing number of studies reporting the overexpression of ENO1 in human cancers, making it a candidate for a promising therapeutic and diagnostic target in various types of cancers [ 9 , 41 , 42 ]. Zhang et al [ 43 ] showed that using cinnamaldehyde (an active ingredient that originates from cinnamon) silences ENO1, arrests the cell cycle, and promotes apoptosis of melanoma cells [ 43 ]. The previously discussed ascorbic acid also interacts with ENO1 and induces the apoptosis of melanoma cells [ 21 ].…”

Atractylenolide-I covalently binds to CYP11B2, selectively inhibits aldosterone synthesis, and improves hyperaldosteronism

“…CETSA was used to detect stability changes in the CYP11B2 protein, according to a previously reported method 28 , 29 . The method is summarized as follows: NCI-H295R cell lysates were treated with AT-I, AT-II, or AT-III (10 μmol/L) for 12 h at different temperatures (37, 40, 43, 46, 49, 52, 55, 58, and 61 °C) or treated with different concentrations of AT-I (0.01, 0.1, 1, 2.5, 5, 10, 20, and 50 μmol/L) for 12 h at 55 °C, and Western blot was used to determine the change in CYP11B2 protein.…”

Cinnamaldehyde Regulates the Generation of γ‐aminobutyric Acid to Exert Sedation via Irreversible Inhibition of ENO1 in the Cerebellar Granular Layer

“…The doses were determined according to previous research. [15,27] Nontargeted Metabolomics Analysis: The plasma of cynomolgus macaques was used for nontargeted metabolomics analysis. Nontargeted ultraperformance liquid chromatography (UPLC)-MS/MS analysis and metabolite identification were performed by Shanghai Applied Protein Technology Co., Ltd. (Shanghai, China), who provided technical support and in-depth discussions.…”

“…Thermal Shift Assay: This experiment was performed as described in reference [15] with some modifications. Briefly, the ENO1_WT and ENO1_S40 recombinant proteins were exposed to 10 μM CA or PA for 4 h at 37°C.…”

“…[12] Diverse investigations have shown that CA exerts various bioactive activities, such as anti-inflammatory, antimicrobial, antidiabetic, anticancer, antiviral, and pain relief. [13][14][15] Furthermore, the effects of CA to alleviate mental illness CA have also been reported. For example, CA exerts anxiolytic and sedative effects in the elevated plus maze and open field tests for mouse behavior.…”