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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Cytokines from the tumor microenvironment modulate sirtinol cytotoxicity in A549 lung carcinoma cells
Shyama Pal1, Bhavani S Shankar, Krishna B Sainis
1Radiation Biology & Health Sciences Division, Bio-Medical Group, Bhabha Atomic Research Centre, Modular Laboratories, Mumbai 400085, India.
Abstract:
Cytokines in tumor microenvironment play an important role in the success or failure of molecular targeted therapies. We have chosen tumor necrosis factor α (TNF-α), TNF related apoptosis inducing ligand (TRAIL), insulin-like growth factor 1 (IGF-1) and transforming growth factor β (TGF-β) as representative pro-inflammatory, pro-apoptotic, anti-apoptotic and anti-inflammatory tumor derived cytokines. Analysis of Oncomine database revealed the differential expression of these cytokines in a subset of cancer patients. The effects of these cytokines on cytotoxicity of FDA approved drugs - cisplatin and taxol and inhibitors of epidermal growth factor receptor - AG658, Janus kinase - AG490 and SIRT1 - sirtinol were assessed in A549 lung cancer cells. TRAIL augmented cytotoxicity of sirtinol and IGF-1 had a sparing effect. Since TRAIL and IGF-1 differentially modulated sirtinol cytotoxicity, further studies were carried out to identify the mechanisms. Sirtinol or knockdown of SIRT1 increased the expression of death receptors DR4 and DR5 and sensitized A549 cells to TRAIL. Increased cell death in presence of TRAIL and sirtinol was caspase independent and demonstrated classical features of necroptosis. Inhibition of iNOS increased caspase activity and switched the mode of cell death to caspase mediated apoptosis. Interestingly, sirtinol or SIRT1 knockdown did not increase IGF-1R expression. Instead, it abrogated ligand induced downregulation of IGF-1R and increased cell survival through PI3K-AKT pathway. In conclusion, these findings reveal that the tumor microenvironment contributes to modulation of cytotoxicity of drugs and that combination therapy, with agents that increase TRAIL signaling and suppress IGF-1 pathway may potentiate anticancer effect.
Insights
Tumor microenvironment cytokines modulate drug effectiveness. Combining TRAIL-boosting agents with IGF-1 pathway suppressors may enhance anticancer therapy by promoting necroptosis or apoptosis.
Area of Science:
- Cancer Biology
- Molecular Oncology
- Drug Development
Background:
- Cytokines within the tumor microenvironment significantly influence the efficacy of molecular targeted therapies.
- Key cytokines including tumor necrosis factor-α (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), insulin-like growth factor-1 (IGF-1), and transforming growth factor-β (TGF-β) exhibit diverse roles in cancer progression.
- Differential expression of these cytokines is observed in various cancer patient subsets.
Purpose of the Study:
- To investigate the impact of specific tumor-derived cytokines (TNF-α, TRAIL, IGF-1, TGF-β) on the cytotoxicity of established anticancer drugs and targeted inhibitors.
- To elucidate the mechanisms by which TRAIL and IGF-1 differentially modulate the effects of sirtinol, a SIRT1 inhibitor, on A549 lung cancer cells.
- To explore potential combination therapeutic strategies targeting the tumor microenvironment for enhanced anticancer effects.
Main Methods:
- Analysis of cytokine expression using the Oncomine database.
- Assessment of drug and inhibitor cytotoxicity in A549 lung cancer cells.
- Investigation of molecular mechanisms including receptor expression, cell death pathways (apoptosis, necroptosis), and signaling pathways (PI3K-AKT).
Main Results:
- TRAIL enhanced sirtinol's cytotoxicity, while IGF-1 exhibited a sparing effect.
- Sirtinol/SIRT1 knockdown sensitized cells to TRAIL by upregulating DR4/DR5, leading to caspase-independent necroptosis.
- Inhibition of iNOS switched cell death to apoptosis; sirtinol/SIRT1 knockdown affected IGF-1R signaling, promoting cell survival via PI3K-AKT.
Conclusions:
- The tumor microenvironment critically modulates drug cytotoxicity, impacting therapeutic outcomes.
- Combination therapies involving agents that enhance TRAIL signaling and inhibit the IGF-1 pathway hold promise for potentiating anticancer effects.
- Understanding cytokine-mediated signaling is crucial for developing effective combination cancer treatments.
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