Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells

Ebony Nottingham; Elizabeth Mazzio; Sunil Kumar Surapaneni; Shallu Kutlehria; Arindam Mondal; Ramesh Badisa; Stephen Safe; Arun K. Rishi; Mandip Singh

doi:10.1016/j.jpha.2021.06.002

Volume 11 Issue 6

Dec. 2021

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Article Navigation > Journal of Pharmaceutical Analysis > 2021 > 11(6): 799-807

Ebony Nottingham, Elizabeth Mazzio, Sunil Kumar Surapaneni, Shallu Kutlehria, Arindam Mondal, Ramesh Badisa, Stephen Safe, Arun K. Rishi, Mandip Singh. Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells[J]. Journal of Pharmaceutical Analysis, 2021, 11(6): 799-807. doi: 10.1016/j.jpha.2021.06.002

Citation:

Ebony Nottingham, Elizabeth Mazzio, Sunil Kumar Surapaneni, Shallu Kutlehria, Arindam Mondal, Ramesh Badisa, Stephen Safe, Arun K. Rishi, Mandip Singh. Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells[J]. Journal of Pharmaceutical Analysis, 2021, 11(6): 799-807. doi: 10.1016/j.jpha.2021.06.002

Citation:

Ebony Nottingham, Elizabeth Mazzio, Sunil Kumar Surapaneni, Shallu Kutlehria, Arindam Mondal, Ramesh Badisa, Stephen Safe, Arun K. Rishi, Mandip Singh. Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells[J]. Journal of Pharmaceutical Analysis, 2021, 11(6): 799-807. doi: 10.1016/j.jpha.2021.06.002

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Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells

doi: 10.1016/j.jpha.2021.06.002

a. Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, 32307, USA;
b. Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A & M University, College Station, TX, 77843, USA;
c. John D. Dingell VA medical Center and Department of Oncology, Wayne State University, Detroit, MI, 48201, USA

Funds:

We thank National Institute on Minority Health and Health Disparities (National Institutes of Health, Grant/Award No.: U54 MD007582) and NSF-CREST Center for Complex Materials Design for Multidimensional Additive Processing (CoManD, Grant/Award No.: 1735968) for providing the funding for this research.

Received Date: May 12, 2020
Accepted Date: Jun. 09, 2021
Rev Recd Date: Jun. 04, 2021
Available Online: Jan. 12, 2022
Publish Date: Dec. 15, 2021

Abstract

Abstract

Non-small cell lung cancer (NSCLC) is often characterized by an underlying mutation in the epidermal growth factor receptor (EGFR), contributing to aggressive metastatic disease. Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate (CDODA-Me), a glycyrrhetinic acid derivative, reportedly improves the therapeutic response to erlotinib (ERL), an EGFR tyrosine kinase inhibitor. In the present study, we performed a series of studies to demonstrate the efficacy of CDODA-Me (2 μM) in sensitizing HCC827R (ERL-resistant) cells to ERL. Herein, we first established the selectivity of ERL-induced drug resistance in the HCC827R cells, which was sensitized when ERL was combined with CDODA-Me (2 μM), shifting the IC₅₀ from 23.48 μM to 5.46 μM. Subsequently, whole transcriptomic microarray expression data demonstrated that the combination of ERL + CDODA-Me elicited 210 downregulated genes (0.44% of the whole transcriptome (WT)) and 174 upregulated genes (0.36% of the WT), of which approximately 80% were unique to the ERL + CDODA-Me group. Synergistic effects centered on losses to cell cycle progression transcripts, a reduction of minichromosome maintenance complex components (MCM2-7), all key components of the Cdc45·MCM2-7GINS (CMG) complex, and replicative helicases; these effects were tantamount to the upregulation of processes associated with the nuclear factor erythroid 2 like 2 translational response to oxidative stress, including sulfiredoxin 1, heme oxygenase 1, and stress-induced growth inhibitor 1. Collectively, these findings indicate that the synergistic therapeutic effects of ERL + CDODA-Me on resistant NSCLC cells are mediated via the inhibition of mitosis and induction of oxidative stress.
- Transcriptomic analysis,
- Combination therapy,
- Drug resistance,
- Erlotinib,
- Epidermal growth factor receptor

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References(63)

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