Synergistic action of Cisplatin and 9-Phenyl acridine in A375 cells

Cisplatin is a widely used chemotherapeutic drug and its potency lead to treatment of different types of cancer. Cisplatin discovery has led to the perception that platinum (II) compounds can be potent anticancer drugs that can successfully use in the treatment of cancers like cancer of bones, muscles, soft tissue, blood, etc. In spite of having such a broad spectrum of anticancer activity, these platinum compounds are poisons, become resistance to different cancers and produce severe side effects. So, cisplatin is often used in combination with other chemotherapeutic agents like PARP inhibitors to increase its efficacy at lower doses. In this report, we present our findings on the effect of 9-Phenyl acridine (ACPH) on cisplatin toxicity in A375 cells. ACPH could sensitize killing of both exponential and density inhibited A375 human melanoma cells. Compared to cisplatin alone, co-treatment of cisplatin with ACPH resulted in an increase in DNA damage, ROS generation and depletion of GSH level in treated cells. Apoptotic death was also enhanced. ACPH possibly potentiated the effects of cisplatin through the inhibition of PARP1 activity.

Some UV-bystander effects are mediated through induction of antioxidant defense in mammalian cells.

Bystander effect is the communication of signals from irradiated to unexposed neighboring cells which is often mediated through factors released from irradiated cells. We have attempted to investigate whether UV-bystander phenomenon can modulate the sensitivity of A375 cells and its mechanism. For this purpose, the conditioned medium from UVC-irradiated cells, which contained these released factors, was used to treat non-exposed cells. These cells were then subsequently treated with UVC or another genotoxicant H2O2. Cell viability was determined by Trypan blue-exclusion assay, DNA damage by flow cytometry analysis, ROS production by flow cytometry and microscopic analysis. Lipid peroxidation and antioxidant defense were assayed biochemically. Our findings revealed that exposure of non-irradiated cells to these factors induced increased in SOD and catalase activities which reverted to normal levels by 8 h. During this period, the released factors-treated cells were resistant to killing by UVC or H2O2 and induced DNA damage and lipid peroxidation were also lowered. This protection from cell killing was not present 8 h after exposure to these released factors. Our results suggested UV-bystander effect increased viability of cells through induction of antioxidant defense. This indicated UV-bystander phenomenon triggers protective response in cells.