2-Methoxyestradiol and Its Combination with a Natural Compound, Ferulic Acid, Induces Melanoma Cell Death via Downregulation of Hsp60 and Hsp90

Abstract

Melanoma is an aggressive type of skin cancer with one of the highest mortality rates. Notably, its incidence in the last few decades has increased faster than any other cancer. Therefore, searching for novel anticancer therapies is of great clinical importance. In the present study, we investigated the anticancer potential of 2-methoxyestradiol, potent chemotherapeutic, in the A375 melanoma cellular model. In order to furthermore evaluate the anticancer efficacy of 2-methoxyestradiol, we have additionally combined the treatment with a naturally occurring polyphenol, ferulic acid. The results were obtained using the melanoma A375 cellular model. In the study, we used MTT assay, flow cytometry, and western blot techniques. Herein, we have evidenced that the molecular mechanism of action of 2-methoxyestradiol and ferulic acid is partly related to the reduction of Hsp60 and Hsp90 levels and the induction of nitric oxide in the A375 melanoma cell model, while no changes were observed in Hsp70 expression after 2-methoxyestradiol and ferulic acid treatment separately or in combination. This is especially important in case of chemoresistance mechanisms because the accumulation of Hsp70 reduces induction of cancer cell death, thus decreasing antitumour efficacy.

2-Methoxyestradiol Damages DNA in Glioblastoma Cells by Regulating nNOS and Heat Shock Proteins

“…It is known, however, that pharmacological concentrations of 2-ME induce caspase 3 in glioblastoma cells of the U87MG line, which indicates the process of apoptosis [ 31 ]. Numerous studies have proven that 2-ME causes apoptosis in other neoplasms, including, among others, melanoma cells [ 37 ], osteosarcoma [ 21 ], prostate [ 38 , 39 ], and breast cells [ 40 ].…”

“…In the presented research, the decreased level of the HSP70 protein under the influence of 2-ME in SW1088 glioblastoma cells was observed. Intriguingly, 2-ME did not affect HSP70 expression in 143B osteosarcoma cells [ 80 ] or in A375 melanoma cells [ 37 ]. HSP70 was shown to prevent the aggregation of oxidized glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and to diminish cell death induced by hypoxia [ 81 ].…”

Ferulic acid regulates miR-17/PTEN axis to inhibit LPS-induced pulmonary microvascular endothelial cells apoptosis through activation of PI3K/Akt pathway

“…FA was shown to accelerate the apoptosis of tumors by regulating heat shock proteins and the PI3K/Akt signaling pathway (Kamm et al, 2019;Luo et al, 2020b). And in ARDS, FA was found to inhibit inflammation and oxidative stress (Zhang et al, 2018).…”

“…Furthermore, FA also was found to against myocardial ischemia/reperfusion (I/R) injury via inhibiting mitophagy which is dependent on PINK1/ Parkin (Luo et al, 2020a). In melanoma cells, FA was observed to be combined with 2-methoxyestradiol to induce cell death by inhibiting Hsp60 and Hsp90 (Kamm et al, 2019). FA induced the apoptosis of cervical carcinoma cells through the Phosphatidylinositol 3-Kinase (PI3K)/Akt Signaling Pathway (Luo et al, 2020b).…”

Heat Shock Protein 60 in Hepatocellular Carcinoma: Insights and Perspectives

“…Recent reports highlight the perspectives of targeting HSP60 as a future tool for cancer treatment (Nakamura and Minegishi, 2013;Cappello et al, 2014;Meng et al, 2018). In fact, HSP60 inhibition has been implemented as a therapeutic strategy in various types of cancers including melanoma (Kamm et al, 2019), pancreatic cancer (Zhou et al, 2018), and ovarian cancer (Guo et al, 2019). However, few reports concerned its targeting in HCC.…”