DUGiDocsThe flavonolignan silibinin in non-small cell lung cancer: molecular mechanisms and therapeutic relevance
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Non-small cell lung cancer (NSCLC) is a challenging disease to treat. Despite several decades of improved clinical progress, there is an unmet need to investigate how therapeutic resistance develops. In particular, managing resistance to targeted therapies such as EGFR and ALK tyrosine kinase inhibitors (TKIs) remains a major challenge. Moreover, the incidence of NSCLC-associated brain metastases is expected to increase due to the increasing number of systemic therapies that are successful extra-cranially but fail to provide therapeutic benefit in the brain. The study of brain metastasis initiation and establishment could reveal new targets and identify novel approaches to address the dismal prognosis and limited therapeutic options in NSCLC patients with brain metastases.
Silibinin, a natural phytochemical found in the milk thistle plant, is beginning to be considered as a biomolecule for the chemopreventive and therapeutic treatment of cancer diseases. This study aimed to comprehensively investigate the effects of silibinin on NSCLC therapeutic resistance and brain metastasis progression based on molecular pharmacology and cancer biology. This study was based on the hypothesis that the multi-targeting behavior of silibinin offers an opportunity to globally affect the multifactorial mechanisms underlying the biological aggressiveness of NSCLC, including therapeutic resistance and the ability to metastasize to the brain.
This study explores the potential of silibinin as a versatile therapeutic agent for the treatment of advanced stage NSCLC. Using an advanced phenotypic drug discovery approach, our study aims to reveal the on-target polypharmacology of silibinin that may contribute to its therapeutic benefits against NSCLC resistance and metastatic dissemination capacity. The objectives of our study are to elucidate the molecular mechanisms of silibinin in reducing the ability of metastatic NSCLC cells in the primary tumor and/or in the brain microenvironment to migrate to the brain, to prevent resistance to targeted therapies, to address side effects of certain drugs, and to characterize its effects on well-established tumor cell intrinsic and microenvironmental drivers of NSCLC brain metastasis
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