اختلال در سلولهای آدنوکارسینوم جهش یافته KRAS ریه
Abstract
1- INTRODUCTION
2- MATERIALS AND METHODS
3- RESULTS
4- DISCUSSION
REFERENCES
Abstract
Objectives: Lung cancer stands out as the most common cancer type worldwide. The most common genetic alteration detected in adenocarcinoma patients is KRAS. KRAS mutated patients still cannot get benefit from precision medicine approaches and lack a targeted therapy. Elesclomol is an investigational agent for melanoma and other malignancies. In this study, we evaluated its effect on cellular apoptosis, survival, and metastasis mechanisms on KRAS mutant A549 and Calu‐1 cell lines.
Methods: The cytotoxic effects of Elesclomol on A549 and Calu‐1 cells were determined by 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) cell viability test. Cells were treated with IC50 concentration and then apoptosis‐ related (Casp‐3, Casp‐9, Bcl‐2, and Bcl‐xL), survival‐related (Akt, p‐Akt, Erk, and p‐ Erk), and metastasis‐related (E‐cadherin, Vimentin, MMP‐2, and MMP‐9) protein expressions were determined by Western blot analysis. Elesclomol’s effect on cell migration was evaluated by wound healing. Total oxidant, malondialdehyde (MDA), and glutathione (GSH) levels after Elesclomol treatment were assessed.
Results: Elesclomol not only induced apoptotic proteins but also inhibited metastatic protein expressions and migration in both cells. Also, p‐Erk activity was diminished by Elesclomol treatment as a reflection of decreased proliferation. However, p‐Akt was enhanced as a cellular survival mechanism. Although Elesclomol’s effects on oxidative stress parameters were puzzling, it induced total oxidant status (TOS), and MDA in Calu‐1 cells.
Conclusion: Elesclomol might provide an alternative treatment approach for patients with KRAS mutant lung adenocarcinoma and other solid tumor malignancies that harbor KRAS mutations. This would enable the development of biomarker‐driven targeted therapy for KRAS mutant adenocarcinoma patients.
INTRODUCTION
Lung cancer stands out as the most common cause of cancer death worldwide. Difficulties in lung cancer treatment mostly arise from the heterogeneity of the disease which multiple genetic mutations exist and their mechanisms are poorly understood. The progress in the “genomic era” has exhibited several genomic alterations that drive the initiation and progression of non–small‐cell lung cancer (NSCLC). Despite being the most commonly mutated oncogene in NSCLC, KRAS mutations remain elusive as a prognostic and predictive marker, such that there is still no approved agent for mutant KRAS in NSCLC. In addition to having a prominent role in energy metabolism, mitochondria is at the crossroads of cell death and survival which has prominent cellular functions required for homeostasis. It not only acts as an oxygen sensor but also as adenosine triphosphate (ATP) and reactive oxygen species (ROS) producer in the cell. As the major source of ROS is the consequence of the mitochondrial respiratory chain reactions, increased ROS production induces apoptosis, thus it makes mitochondria an attractive target for cancer chemotherapy. Triggering mitochondrial oxidative stress might offer new routes to target cancer cells for therapeutic interventions.