Blockade of GCH1-BH4 Axis in KR Cell Line

Glioblastomas (GBM) are the most aggressive form of tumor in the Central Nervous System, with a median survival of 12–18 months and fewer than 5% surviving beyond five years. Additionally, GBM cells have shown to be resistant to radiation treatment, highlighting the need for novel therapeutic approaches. A form of induced cell death called Ferroptosis has been proven to be effective against GBM. Certain drugs, such as RSL3 and IKE, can sensitize cancerous cells to ferroptosis. A novel study proved that colorectal cancer cells are heavily sensitized to ferroptosis through combination of drugs IKE and DAHP more so than through the combination of drugs RSL3 and DAHP. Furthermore, deprivation of amino acids cysteine and methionine in cells has proven to further sensitize the cell to ferroptosis. This study investigated the combinatory ferroptotic sensitization methods of DAHP + RSL3/IKE, with and without cysteine and methionine in the KR GBM cell line. The study was split into 3 phases: proving the cell death was ferroptosis induced by testing against a control ferroptosis inhibitor, confirming DAHP’s genetic knockdown of the BH4-GCH1 pathway through an siRNA knockdown experiment, and finally testing the combinatory effects of DAHP + IKE/RSL3 with and without cysteine and methionine. Upon experimentation, it was discovered that DAHP itself causes cell death through a mechanism other than ferroptosis. Rather, DAHP sensitizes the cell to ferroptosis, and when used in combination with RSL3/IKE, ferroptotic death is observed. Contrary to the paper, the DAHP + RSL3 treatment worked more effectively than the DAHP + IKE treatment. Additionally, placing the two combinatory treatments under cysteine methionine deprived conditions further sensitized the cell to ferroptosis.