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Effects of c-myc oncogene modulation on drug resistance in human small cell lung carcinoma cell lines
R C Van Waardenburg1, J Prins, C Meijer
1Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
Abstract:
Small cell lung carcinoma (SCLC) is characterized by rapid development of resistance to drugs, such as cisdiamminedichloroplatinum (II) (cDDP) and anthracyclines. The molecular basis for resistance to cDDP and adriamycin (Adr) is poorly understood. One of the genetic alterations observed in SCLC, which is correlated with poor prognosis, is amplification and overexpression of c-myc oncogene. Therefore, activation of the c-myc oncogene might form a basis for resistance. The relationship between c-myc and cDDP as well as Adr resistance was analyzed by down-regulation of endogenously expressed c-myc in the human SCLC cell line GLC4, and its cDDP and Adr resistant sublines (GLC4-cDDP and GLC4-Adr). Cells were incubated with an unmodified antisense (AS) oligodeoxynucleotide complementary to the first 5 codons of the c-myc mRNA in serum free culture medium. Pre-incubation with 15 microM AS c-myc, reduced c-myc protein expression and induced 30-35% growth inhibition in all 3 cell lines. It resulted in increased cDDP sensitivity in GLC4-cDDP but not in GLC4. However, this pre-incubation did not affect Adr sensitivity in all lines. The effect of AS c-myc pretreatment on cDDP resistance was not mediated by changes in cell cycle distribution. These findings suggest that c-myc plays a role in cDDP resistance by effects other than those on cell cycle distribution.
Insights
Small cell lung carcinoma (SCLC) develops drug resistance. Down-regulating the c-myc oncogene in SCLC cells increased sensitivity to cisdiamminedichloroplatinum (II) (cDDP), suggesting c-myc’s role in cDDP resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Small cell lung carcinoma (SCLC) exhibits rapid resistance to chemotherapy agents like cisdiamminedichloroplatinum (II) (cDDP) and anthracyclines.
- The molecular mechanisms underlying cDDP and adriamycin (Adr) resistance in SCLC remain largely unelucidated.
- Amplification and overexpression of the c-myc oncogene are observed in SCLC and correlate with poor prognosis, suggesting its potential role in drug resistance.
Purpose of the Study:
- To investigate the relationship between c-myc oncogene activation and resistance to cDDP and Adr in SCLC.
- To determine if down-regulating c-myc expression can alter drug sensitivity in SCLC cell lines.
Main Methods:
- Utilized the human SCLC cell line GLC4 and its cDDP-resistant (GLC4-cDDP) and Adr-resistant (GLC4-Adr) sublines.
- Down-regulated endogenous c-myc expression using an unmodified antisense (AS) oligodeoxynucleotide complementary to the first 5 codons of c-myc mRNA.
- Incubated cells in serum-free medium with 15 microM AS c-myc and assessed effects on protein expression, growth inhibition, drug sensitivity, and cell cycle distribution.
Main Results:
- Pre-incubation with AS c-myc effectively reduced c-myc protein expression in all three cell lines.
- A 30-35% growth inhibition was observed across all tested cell lines following AS c-myc treatment.
- AS c-myc pre-treatment enhanced cDDP sensitivity in the GLC4-cDDP subline but did not affect sensitivity in the parental GLC4 line.
- Adriamycin (Adr) sensitivity remained unaffected by AS c-myc pre-treatment in all cell lines.
- The observed effects of AS c-myc on cDDP resistance were independent of alterations in cell cycle distribution.
Conclusions:
- The c-myc oncogene plays a significant role in conferring resistance to cisdiamminedichloroplatinum (II) (cDDP) in small cell lung carcinoma (SCLC).
- The mechanism by which c-myc influences cDDP resistance involves pathways distinct from cell cycle regulation.
- Targeting c-myc may offer a potential therapeutic strategy to overcome cDDP resistance in SCLC.