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Factors determining sensitivity or resistance of tumor cell lines towards artesunate
Serkan Sertel1, Tolga Eichhorn, Sebastian Sieber
1Department of Otorhinolaryngology, Head & Neck Surgery, University of Heidelberg, Heidelberg, Germany.
Abstract:
Clinical oncology is still challenged by the development of drug resistance of tumors that result in poor prognosis for patients. There is an urgent necessity to understand the molecular mechanisms of resistance and to develop novel therapy strategies. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We first applied a gene-hunting approach using cluster and COMPARE analyses of microarray-based transcriptome-wide mRNA expression profiles. Among the genes identified by this approach were genes from diverse functional groups such as structural constituents of ribosomes (RPL6, RPL7, RPS12, RPS15A), kinases (CABC1, CCT2, RPL41), transcriptional and translational regulators (SFRS2, TUFM, ZBTB4), signal transducers (FLNA), control of cell growth and proliferation (RPS6), angiogenesis promoting factors (ITGB1), and others (SLC25A19, NCKAP1, BST1, DBH, FZD7, NACA, MTHFD2). Furthermore, we applied a candidate gene approach and tested the role of resistance mechanisms towards established anti-cancer drugs for ART resistance. By using transfected or knockout cell models we found that the tumor suppressor p16(INK4A) and the anti-oxidant protein, catalase, conferred resistance towards ART, while the oncogene HPV-E6 conferred sensitivity towards ART. The tumor suppressor p53 and its downstream protein, p21, as well as the anti-oxidant manganese-dependent superoxide dismutase did not affect cellular response to ART. In conclusion, our pharmacogenomic approach revealed that response of tumor cells towards ART is multi-factorial and is determined by gene expression associated with either ART sensitivity or resistance. At least some of the functional groups of genes (e.g. angiogenesis promoting factors, cell growth and proliferation-associated genes signal transducers and kinases) are also implicated in clinical responsiveness of tumors towards chemotherapy. It merits further investigation, whether ART is responsive in clinically refractory tumors and whether the genes identified in the present study also determine clinical responsiveness towards ART.
Insights
Artesunate (ART) drug resistance in cancer is complex. This study identified genes affecting ART sensitivity and resistance, offering new therapeutic strategies for drug-resistant tumors.
Area of Science:
- Pharmacogenomics
- Cancer Biology
- Drug Resistance Mechanisms
Background:
- Clinical oncology faces challenges with tumor drug resistance, necessitating understanding of molecular mechanisms and novel therapies.
- Artesunate (ART), an antimalarial drug, exhibits significant cytotoxic effects against cancer cells, indicating its therapeutic potential.
Purpose of the Study:
- To investigate the molecular mechanisms underlying tumor cell response to Artesunate (ART).
- To identify genes associated with ART sensitivity and resistance using a pharmacogenomic approach.
- To explore potential novel therapeutic strategies for overcoming drug resistance in cancer.
Main Methods:
- Utilized cluster and COMPARE analyses of microarray-based transcriptome-wide mRNA expression profiles for gene-hunting.
- Applied a candidate gene approach to test resistance mechanisms against established anti-cancer drugs for ART resistance.
- Employed transfected and knockout cell models to validate the role of specific genes in ART response.
Main Results:
- Identified diverse functional groups of genes influencing ART response, including ribosomal proteins, kinases, transcriptional regulators, signal transducers, and angiogenesis factors.
- Found that the tumor suppressor p16(INK4A) and catalase confer ART resistance.
- Demonstrated that the oncogene HPV-E6 confers ART sensitivity, while p53, p21, and manganese-dependent superoxide dismutase did not significantly affect ART response.
Conclusions:
- Tumor cell response to ART is multifactorial, determined by a complex interplay of gene expression related to sensitivity and resistance.
- Identified gene groups (e.g., angiogenesis, cell proliferation, signal transduction, kinases) are implicated in clinical chemotherapy response.
- Further investigation is warranted to determine ART's efficacy in refractory tumors and the role of identified genes in clinical ART responsiveness.
