New Paradigms to Assess Consequences of Long-Term, Low-Dose Curcumin Exposure in Lung Cancer Cells.

Gintare Smagurauskaite,Karen Brown,Jagdish Mahale,Anne L Thomas,Lynne M Howells

doi:10.3390/molecules25020366

Gintare Smagurauskaite, Karen Brown + Show 3 more

Open Access

https://doi.org/10.3390/molecules25020366

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Abstract

Curcumin has been investigated extensively for cancer prevention, but it has been proposed that long-term treatments may promote clonal evolution and gain of cellular resistance, potentially rendering cancer cells less sensitive to future therapeutic interventions. Here, we used long-term, low-dose treatments to determine the potential for adverse effects in non-small cell lung cancer (NSCLC) cells. IC50s for curcumin, cisplatin, and pemetrexed in A549, PC9, and PC9ER NSCLC cells were evaluated using growth curves. IC50s were subsequently re-assessed following long-term, low-dose curcumin treatment and a three-month treatment withdrawal period, with a concurrent assessment of oncology-related protein expression. Doublet cisplatin/pemetrexed-resistant cell lines were created and the IC50 for curcumin was determined. Organotypic NSCLC-fibroblast co-culture models were used to assess the effects of curcumin on invasive capacity. Following long-term treatment/treatment withdrawal, there was no significant change in IC50s for the chemotherapy drugs, with chemotherapy-resistant cell lines exhibiting similar sensitivity to curcumin as their non-resistant counterparts. Curcumin (0.25–0.5 µM) was able to inhibit the invasion of both native and chemo-resistant NSCLC cells in the organotypic co-culture model. In summary, long-term curcumin treatment in models of NSCLC neither resulted in the acquisition of pro-carcinogenic phenotypes nor caused resistance to chemotherapy agents.

Highlights

Lung cancer is the most commonly diagnosed cancer worldwide, and is the leading cause of cancer mortality [1]
Whilst lung cancer prevention is primarily focused around smoking cessation, there may still be a role for therapeutic prevention approaches in certain high-risk cohorts
Sensitivity to single-agent cisplatin and pemetrexed in native cell lines, cells treated for 3 months with 0.25 μM of curcumin, and cells that had a subsequent three-month withdrawal of curcumin are shown in Table 1 and Supplemental Figure S1A,B

Summary

Introduction

Lung cancer is the most commonly diagnosed cancer worldwide, and is the leading cause of cancer mortality [1]. Whilst lung cancer prevention is primarily focused around smoking cessation, there may still be a role for therapeutic prevention (chemoprevention) approaches in certain high-risk cohorts. Therapeutic prevention strategies have had little success in lung cancer, with two large trials (alpha-tocopherol and beta-carotene (ATBC), beta-carotene and retinol (CARET)) showing increased mortality in smokers following beta-carotene intervention [3,4]. Subsequent investigations suggested that beta-carotene and its metabolites may contribute to neutrophil-induced genotoxicity in smokers [5], with smoking being a risk factor in itself, independent from inhaled levels of tar and nicotine [6]. Chemoprevention trials are often in healthy populations

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