Novel Indole-based Tambjamine-Analogues Induce Apoptotic Lung Cancer Cell Death through p38 Mitogen-Activated Protein
Pilar Manuel-Manresa1, Luís Korrodi-Gregório1,2, Elsa Hernando3
1Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
Abstract:
Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of BCL2 and BIRC5/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several proapoptotic markers (caspase-9, caspase-3, and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the prosurvival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer. Mol Cancer Ther; 16(7); 1224-35. ©2017 AACR.
Insights
Novel indole-based tambjamine analogues induce lung cancer cell death through apoptosis and oxidative stress. These compounds show significant therapeutic effects in preclinical lung cancer models, offering new hope for treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer is a leading global cause of cancer death, driven by late diagnosis and limited effective treatments.
- Novel natural-derived tambjamine analogues function as potent anion transporters, disrupting cellular ion balance.
- The precise molecular mechanisms underlying the cytotoxic effects of these tambjamine analogues were previously unknown.
Purpose of the Study:
- To elucidate the molecular cell responses and mechanisms of action of indole-based tambjamine analogues in lung cancer cells.
- To investigate the role of apoptosis, oxidative stress, and specific signaling pathways in tambjamine analogue-induced cell death.
- To evaluate the therapeutic efficacy of these compounds in preclinical lung cancer models.
Main Methods:
- Gene expression analysis to identify affected pathways (apoptosis, cell cycle, growth factors).
- Assessment of apoptotic markers (caspase-9, caspase-3, PARP) and Bcl-2 family protein expression.
- Measurement of reactive oxygen species (ROS) production and p38 MAPK pathway activation.
- In vivo studies using subcutaneous and orthotopic lung cancer mouse models.
Main Results:
- Tambjamine analogues induced significant changes in genes related to apoptosis, cell cycle, and growth factors, notably downregulating BCL2 and BIRC5/survivin.
- Activation of proapoptotic markers and a decrease in prosurvival Bcl-2 members confirmed apoptosis induction.
- Compounds caused ROS accumulation and activated the p38 MAPK pathway, both crucial for cytotoxicity.
- Significant therapeutic effects were observed in both subcutaneous and orthotopic lung cancer mouse models.
Conclusions:
- Indole-based tambjamine analogues trigger lung cancer cell death via apoptosis and oxidative stress, involving the p38 MAPK pathway.
- These novel cytotoxic anionophores demonstrate promising therapeutic potential against lung cancer in preclinical settings.
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