Lapatinib: A Potential Therapeutic Agent for Colon Cancer Targeting Ferroptosis.

Background: Colon cancer poses a significant threat to the lives of several patients, impacting their quality of life, thus necessitating its urgent treatment. Lapatinib, a new generation of targeted anti-tumor drugs for clinical application, has yet to be studied for its molecular mechanisms in treating colon cancer.

Objectives: This study aimed to uncover the underlying molecular mechanisms through which lapatinib exerts its therapeutic effects in colon cancer treatment.

Methods: We accessed pertinent data on patients with colon cancer from the Cancer Genome Atlas (TCGA) database and performed bioinformatics analysis to derive valuable insights. The cell counting kit-8 (CCK8) assay was employed to assess whether lapatinib has a potential inhibitory effect on the growth and proliferation of HT- 29 cells. Additionally, we employed western blot and real-time quantitative polymerase chain reaction methods to investigate whether lapatinib regulates the expression of the ferroptosis-associated protein GPX4 in HT-29 cells. Furthermore, we utilized specific assay kits to measure the levels of reactive oxygen species (ROS) and malondialdehyde in HT-29 cells treated with lapatinib, aiming to elucidate the precise pattern of cell damage induced by this compound.

Results: GPX4 exhibited high expression levels in tissues from patients with colon cancer and was significantly associated with patient prognosis and diagnosis. Lapatinib inhibited the growth and proliferation of the colon cancer cell line HT-29. Additionally, lapatinib suppressed the expression of GPX4 in HT-29 cells, while the ferroptosis inhibitor ferrostatin-1 (Fer-1) partially restored its expression. Lapatinib induced an increase in intracellular ROS levels and malondialdehyde content in HT-29 cells, with Fer-1 partially restoring these levels.

Conclusion: Our findings demonstrated that lapatinib could effectively suppress the mRNA and protein expression of GPX4 in colon cancer cells, which elevates intracellular levels of ROS and malondialdehyde, ultimately inducing ferroptosis in these cells. This mechanism underscores the potential of lapatinib as a therapeutic strategy for targeting tumors.