Abstract:
Platinum-based compounds are considered as the backbone of chemotherapy for different types of cancer. Since all currently available chemotherapeutic drugs still suffer from serious side effects, the need for new efficient and safe drugs is of prime importance. The present study aims to investigate the anticancer effect of two novel platinum-based drugs AK1 (Pt II-based) and AK2 (Pt IV-based) on A549 lung cancer cells and elucidate the mechanism of action involved. WSTassay was used to assess cell viability. Results revealed a minimum inhibitory concentration (IC50) of 8.4 μM for AK1 and 43.38 μM for AK2 when tested on A549 cells. Similar studies were conducted on isolated rat bone marrow mesenchymal stem cells and showed IC50 values of 6.544 μM for AK1 and >124.4 μM for AK2. Cellular uptake of both drugs using the ICP-MS revealed that both drugs use active transport, with AK1 having a faster and higher uptake than AK2. Using comet assay, it was demonstrated that both drugs cause DNA fragmentation with AK2 having more DNA damage than AK1. Flow cytometry analysis showed that apoptosis is the mode of cells death with both drugs. Western blots experiments were also carried out to observe the effect of the drugs on key apoptotic proteins. Data revealed a significant drop in procaspase 3 and a significant increase in Bax/Bcl2 ratio, Cytochrome c, Parp and procaspase 8. In conclusion, both Ak1 and AK2 induce apoptosis through the intrinsic pathway. While AK1 exhibited faster uptake and greater cytotoxicity, AK2 was by far less toxic to normal mesenchymal stem cells. Further in vivo studies are needed to confirm the efficacy and safety of AK1 and AK2.
