3, 3'- (3, 5-DCPBC) Down-Regulates Multiple Phosphokinase Dependent Signal Transduction Pathways in Malignant Melanoma Cells through Specific Diminution of EGFRY1086 Phosphorylation.

Qurat-Ul-Ain Qurat-Ul-Ain,Abhijit Basu,Karin Scharffetter-Kochanek,M Iqbal Choudhary

doi:10.3390/molecules27041172

Abstract

Melanoma is the most dangerous skin malignancy due to its strong metastatic potential with high mortality. Activation of crucial signaling pathways enforcing melanoma progression depends on phosphorylation of distinct tyrosine kinases and oxidative stress. We here investigated the effect of a bis-coumarin derivative [3, 3′- ((3″, 5′-Dichlorophenyl) methylene) bis (4-hydroxy-2H-chromen-2-one)] [3, 3′- (3, 5-DCPBC)] on human melanoma cell survival, growth, proliferation, migration, intracellular redox state, and deciphered associated signaling pathways. This derivative is toxic for melanoma cells and non-toxic for melanocytes, their benign counterpart, and fibroblasts. 3, 3′- (3, 5-DCPBC) inhibits cell survival, migration, and proliferation of different metastatic and non-metastatic melanoma cell lines through profound suppression of the phosphorylation of Epidermal Growth Factor receptor (EGFR) and proto-oncogene cellular sarcoma (c-SRC) related downstream pathways. Thus, 3, 3′- (3, 5-DCPBC) endowed with the unique property to simultaneously suppress phosphorylation of multiple downstream kinases, such as EGFR/JAK/STAT and EGFR/SRC and their corresponding transcription factors.

Highlights

Malignant melanoma represents the most aggressive and deadliest form of skin cancer [1,2,3]
Due to severe and in part lifethreatening side effects of immune checkpoint inhibitors affecting up to 50% of melanoma patients treated with anti-CTLA-4 immunotherapy [14], and even more when subjected to a combined anti-CTLA-4 and anti-PD-1 therapy [15], there is an urgent quest for new strategies in the battle against metastatic melanoma
We demonstrated that treatment of human metastatic and non-metastatic melanoma cells with 3, 3 - (3, 5-DCPBC) profoundly diminished phosphorylation of the Epidermal Growth Factor Receptor (EGFR), proto-oncogene cellular sarcoma (c-SRC) and simultaneously suppressed phosphorylation of key downstream effectors and signaling pathways known to enforce melanoma progression

Summary

Introduction

Malignant melanoma represents the most aggressive and deadliest form of skin cancer [1,2,3]. Surgery still represents the first treatment option for primary melanoma where metastasis has not yet occurred. The most successful treatment options against non-resettable metastatic melanoma are immunotherapies with antibodies directed against CTLA-4 and PD-1 [6,7] or their combination (small kinase and checkpoint inhibitors) [8,9,10]. Due to the resistant nature of malignant melanoma [12], 40% of the patients do not respond to the combined therapy [13]. Due to severe and in part lifethreatening side effects of immune checkpoint inhibitors affecting up to 50% of melanoma patients treated with anti-CTLA-4 immunotherapy [14], and even more when subjected to a combined anti-CTLA-4 and anti-PD-1 therapy [15], there is an urgent quest for new strategies in the battle against metastatic melanoma. Several promising agents have been tested against single protein kinases in malignancies [16,17]

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Conclusion