Overcoming resistance in lung cancer: combined mitochondrial destabilization by lipophilic cations and doxycycline in hypoxic non-small cell lung carcinoma.

Introduction: Lung cancer remains the leading cause of cancer-related mortality worldwide. Drug resistance is a major limitation of current therapies, prompting the search for new treatment strategies. Lung tumors frequently develop a hypoxic microenvironment associated with aggressive behavior and unfavorable clinical outcomes. Tumor-initiating cells (TICs), also known as cancer stem cells, and hypoxia-driven metabolic adaptations contribute significantly to therapy resistance. Mitochondrial destabilization has emerged as a promising invariant target in TICs. Triphenylphosphonium (TPP Methods: TPP Results: Our results demonstrate that these compounds exhibit cytotoxicity in lung cancer cells, particularly under hypoxic conditions, consistent with mitochondrial functional impairment. Combinations of TPP Conclusion: Targeting mitochondrial functions using mitochondria-directed compounds, particularly in combination with doxycycline, represents a promising therapeutic approach for lung cancer. This strategy may be especially effective in hypoxic microenvironments, where conventional therapies often fail. Further