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A Novel Inhibitor of Topoisomerase I Is Selectively Toxic for a Subset of Non-Small Cell Lung Cancer Cell Lines.

ABSTRACT: SW044248, identified through a screen for chemicals that are selectively toxic for non-small cell lung cancer (NSCLC) cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive, cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was nontoxic to immortalized human bronchial cell lines. The acute transcriptional response to SW044248 in sensitive HCC4017 cells correlated significantly with inhibitors of topoisomerases and SW044248 inhibited topoisomerase 1 (Top1) but not topoisomerase 2. SW044248 inhibited Top1 differently from camptothecin and camptothecin did not show the same selective toxicity as SW044248. Elimination of Top1 by siRNA partially protected cells from SW044248, although removing Top1 was itself eventually toxic. Cells resistant to SW044248 responded to the compound by upregulating CDKN1A and siRNA to CDKN1A sensitized those cells to SW044248. Thus, at least part of the differential sensitivity of NSCLC cells to SW044248 is the ability to upregulate CDKN1A.

SUBMITTER: Zubovych IO

PROVIDER: S-EPMC4707128 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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A Novel Inhibitor of Topoisomerase I Is Selectively Toxic for a Subset of Non-Small Cell Lung Cancer Cell Lines.

Zubovych Iryna O IO Sethi Anirudh A Kulkarni Aditya A Tagal Vural V Roth Michael G MG

Molecular cancer therapeutics 20151214 1

SW044248, identified through a screen for chemicals that are selectively toxic for non-small cell lung cancer (NSCLC) cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive, cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was nontoxic to immortalized human bronchial cell lines. The acute transcriptional response to SW044248 in sensitive HCC4017 cells correlated significantly with inhibitors of topoisomerases and SW044 ...[more]

PMID: 26668189

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Project description:ImportanceImmunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non-small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy.ObjectiveTo gain mechanistic insight into autoimmune skin toxic effects induced by anti-PD-1 treatment in patients with non-small cell lung cancer.Design, setting, and participantsThis prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non-small cell lung cancer who received anti-PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year.Main outcomes and measuresResponse to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations).ResultsOf the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ2 = 14.02, P < .001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti-PD-1 therapy.Conclusions and relevanceThese findings highlight a potential mechanism of checkpoint inhibitor-mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy.

Project description:BackgroundIMMUNEPOTENT-CRP® (I-CRP) is a bovine dialyzable leukocyte extract containing transfer factor. It is a cost-effective, unspecific active immunotherapy that has been used in patients with non-small cell lung cancer (NSCLC) as an adjuvant to reduce the side-effects of chemotherapy and radiotherapy, and has shown cytotoxic activity in vitro on different cancer cell lines. However, its mechanism of action against lung cancer cells has not been assessed. Therefore, the objective of this work was to assess the cytotoxic mechanism of I-CRP on lung cancer cell lines.MethodsWe assessed cell viability through MTT assay on the NSCLC cell lines A549, A427, Calu-1, and INER-51 after treatment with I-CRP. To further understand the mechanisms of cell viability diminution we used fluorescence-activated cell sorting to evaluate cell death (annexin-V and propidium iodide [PI] staining), cell cycle and DNA degradation (PI staining), mitochondrial alterations (TMRE staining), and reactive oxygen species (ROS) production (DCFDA staining). Additionally, we evaluated caspase and ROS dependence of cell death by pretreating the cells with the pan-caspase inhibitor Q-VD-OPH and the antioxidant N-acetylcysteine (NAC), respectively.ResultsOur data shows that I-CRP is cytotoxic to NSCLC cell lines in a dose and time dependent manner, without substantial differences between the four cell lines tested (A549, A427, Calu-1, and INER-51). Cytotoxicity is induced through regulated cell death and cell cycle arrest induction. I-CRP-induced cell death in NSCLC cell lines is characterized by DNA degradation, mitochondrial damage, and ROS production. Moreover, cell death is independent of caspases but relies on ROS production, as it is abrogated with NAC.ConclusionAltogether, these results improve the knowledge about the cytotoxic activity of I-CRP on NSCLC cells, indicating that cell death, cell cycle arrest, DNA degradation and mitochondrial damage are important features, while ROS play the main role for I-CRP mediated cytotoxicity in lung cancer cells.

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A Novel Inhibitor of Topoisomerase I Is Selectively Toxic for a Subset of Non-Small Cell Lung Cancer Cell Lines.

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A Novel Inhibitor of Topoisomerase I Is Selectively Toxic for a Subset of Non-Small Cell Lung Cancer Cell Lines.

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