Gene-drug combination strategy for induction of apoptosis and ferroptosis on lung cancer cell line

Abstract

Introduction: Platinum-based chemotherapies are commonly used anti-cancer agents. However, chemoresistance is the main reason for Platinum-based drugs failure. Cancer cells' anti-apoptotic signaling is one of the most prevalent strategies for drug resistance induction. Therefore, in this research, different types of programmed cell death strategies (apoptosis and ferroptosis) are investigated to overcome Platinum-based drugs resistance in the lung and colorectal cancer models. Objective: To examine different cell death strategies (apoptosis and ferroptosis) to overcome drug resistance through gene and chemo-gene therapies. Materials and method: The Akt1 and Gpx4, as critical regulators of apoptosis and ferroptosis, were knocked down by siRNA using a Hiperfect transfection reagent. Apoptosis and ferroptosis confirmation tests were performed to evaluate the effect of each strategy on A549, HT-29, and Caco-2 resistance cell lines. Meanwhile, the impact of treatments on the expression of Akt1, Gpx4, Nrf2, and CoQ10 genes was analyzed by real-time PCR. Finally, the effect of combination treatment on resistant cancer cells eradication was measured by trypan blue exclusion dye assay. Results and discussion: We noticed that ferroptosis induction through either Gpx4 siRNA or FIN56 reversed the platinum-based drug resistance. Results showed that ferroptosis induction using GPX4 silencing or FIN56 could eradicate resistance cells by 92% and 85%, respectively. Similarly, induction of apoptosis by silencing Akt1 siRNA and its combination with cisplatin/oxaliplatin has improved chemo-drug efficiency in the resistant cancer cell lines; this treatment eradicated about 85% of the cells. Finally, comparing the effects of these strategies has indicated that both apoptosis and ferroptosis induction can be applied in fighting resistance cancer cells. Conclusion: The achieved data indicate that ferroptosis can be an effective cell death strategy to overcome chemo-resistant cancer cells.