Apoptosis Induced by 2-Aryl Benzothiazoles-Mediated Photodynamic Therapy in Melanomas via Mitochondrial Dysfunction

Abstract

A mild and efficient synthetic development of 2-arylbenzothiazoles 5 mediated by ceric ammonium nitrate (CAN) via intramolecular cyclization of N-phenyl-thiobenzamides 4 was achieved. Further compounds 5 were reduced to corresponding amines 6, and their photodynamic therapy (PDT) effect was evaluated on malignant human melanoma A375 cells. Amine 6l plus ultraviolet A (UVA) induced caspase-3 activity, poly(ADP-ribose)polymerase cleavage, M30 positive CytoDeath staining, and subsequent apoptotic cell death. Our data disclosed that treatment of A375 cells with 6l plus UVA resulted in a decrease in mitochondrial membrane potential (ΔΨmt), oxidative phosphorylation system (OXPHOS) subunits, and adenosine triphosphate (ATP) but an increase in mitochondrial DNA 4977-bp deletion via reactive oxygen species (ROS) generation. Transmission electron microscopy (TEM) observations also showed major ultrastructural alterations of mitochondria. Additionally, 6l plus UVA was also shown to reduce murine melanoma size in a mouse model. The present study supports the hypothesis that 6l-PDT may serve as a potential ancillary modality for the treatment of melanoma.

Cancer Tissue Classification, Associated Therapeutic Implications and PDT as an Alternative

“…Non-specific Cellular Damage. The critical homeostasis of biomolecule concentrations for healthy cell function include ROS as signaling mediators of multiple cellular pathways that regulate survival, proliferation and cell death (92,93,94). However, excessive levels damage various cellular components including protein structure and activity (95), membrane integrity and dysfunction of trans-membrane protein channels (96), and nucleic acid lesions, base modifications and protein-DNA cross linking (8,95,97).…”

“…However, excessive levels damage various cellular components including protein structure and activity (95), membrane integrity and dysfunction of trans-membrane protein channels (96), and nucleic acid lesions, base modifications and protein-DNA cross linking (8,95,97). This broad scale damage is responsible for numerous diseases including carcinogenesis (93,98,99). ROS levels are, therefore, tightly regulated (i.e.…”

Enoxacin with UVA Irradiation Induces Apoptosis in the AsPC1 Human Pancreatic Cancer Cell Line Through ROS Generation

“…We considered the possibility that UVA radiation could be used for the treatment of cancer in the form of photodynamic therapy (PDT). Several drugs have been investigated for their ability to act as photosensitizing agents for PDT; these drugs were found to induce apoptosis of cancer cells (8)(9)(10).…”

Mechanistics and photo‐energetics of macrocycles and photodynamic therapy: An overview of aspects to consider for research

“…A well‐established law of nature is the critical homoeostasis of biomolecule concentrations for healthy cell function. ROS are no exception and are typically generated within cells as signalling mediators of multiple cellular pathways that regulate survival, proliferation and cell death . Excessive levels damage proteins, lipids and nucleic acids and are responsible for numerous diseases including carcinogenesis .…”

“…ROS are no exception and are typically generated within cells as signalling mediators of multiple cellular pathways that regulate survival, proliferation and cell death . Excessive levels damage proteins, lipids and nucleic acids and are responsible for numerous diseases including carcinogenesis . ROS levels are therefore tightly regulated via neutralization with antioxidant defence mechanisms, free radical scavenger molecules and endogenous antioxidant enzymes .…”