Lenalidomide induces apoptosis and alters gene expression in non-small cell lung cancer cells

Kim,Karam; An,Sungkwan; Cha,Hwa   Jun; Choi,Yeong  Min; Choi,Sung  Jin; An,In-Sook; Lee,Hong   Ghi; Min,Yoo   Hong; Lee,Su-Jae; Bae,Seunghee

doi:10.3892/ol.2012.1054

Lenalidomide induces apoptosis and alters gene expression in non-small cell lung cancer cells

Authors:
- Karam Kim
- Sungkwan An
- Hwa Jun Cha
- Yeong Min Choi
- Sung Jin Choi
- In-Sook An
- Hong Ghi Lee
- Yoo Hong Min
- Su-Jae Lee
- Seunghee Bae
View Affiliations

Affiliations: Molecular-Targeted Drug Research Center, Konkuk University, Gwangjin-gu, Seoul 143-701, Republic of Korea, Korea Institute for Skin and Clinical Sciences, Konkuk University, Gwangjin-gu, Seoul 143-701, Republic of Korea, Department of Internal Medicine, Konkuk University College of Medicine, Seoul 143-729, Republic of Korea, Department of Internal Medicine and Center for Chronic Metabolic Disease, Yonsei University College of Medicine, Seoul 102-752, Republic of Korea, Department of Chemistry, Hanyang University, Seongdong-gu, Seoul 133-791, Republic of Korea
Published online on: November 30, 2012 https://doi.org/10.3892/ol.2012.1054
Pages: 588-592

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Non-small cell lung cancer (NSCLC) is the most deadly type of cancer worldwide. Although a number of therapies are used in NSCLC treatment, their therapeutic efficacy remains low. Lenalidomide was originally approved for use in patients with myelodysplastic syndromes, which are associated with 5q deletions, and multiple myeloma. Recently, lenalidomide was investigated as a new NSCLC treatment, and it exerted anticancer effects. However, the primary cellular mechanism of its effects in NSCLC is largely unknown. Therefore, we attempted to elucidate a molecular portrait of lenalidomide-mediated cellular events in NSCLC. Lenalidomide reduced the viability of several NSCLC cell lines in a concentration-dependent manner. In addition, array-based gene expression analysis revealed that lenalidomide regulated the expression of several genes associated with cell survival, apoptosis and development, including BH3-interacting domain death agonist (BID), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) and NK2 homeobox1 (NKX2-1). BID and FOS, which are known apoptosis activators, were upregulated by lenalidomide treatment, whereas NKX2-1, which is used as an immunohistochemistry marker for NSCLC, was downregulated. These results provide evidence that lenalidomide directly induces antiproliferative effects by altering the expression of genes associated with cell proliferation and apoptosis.

View Figures

View References

1.	Ferlay J, Shin HR, Bray F, et al: GLOBOCAN 2008, Cancer incidence and mortality worldwide. IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer; 2010, http://globocan.iarc.fr.
2.	American Cancer Society: 2010 Cancer facts and figures. Atlanta, GA: American Cancer Society; 2010
3.	Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Engl J Med. 359:1367–1380. 2008. View Article : Google Scholar : PubMed/NCBI
4.	List A, Kurtin S, Roe DJ, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 352:549–557. 2005. View Article : Google Scholar : PubMed/NCBI
5.	Hideshima T, Richardson PG and Anderson KC: Current therapeutic uses of lenalidomide in multiple myeloma. Expert Opin Investig Drugs. 15:171–179. 2006. View Article : Google Scholar : PubMed/NCBI
6.	Eisen T, Trefzer U, Hamilton A, et al: Results of a multicenter, randomized, double-blind phase 2/3 study of lenalidomide in the treatment of pretreated relapsed or refractory metastatic malignant melanoma. Cancer. 116:146–154. 2010.
7.	Kalmadi S, Davis M, Dowlati A, et al: Phase I trial of three-weekly docetaxel, carboplatin and oral lenalidomide (Revlimid) in patients with advanced solid tumors. Invest New Drugs. 25:211–216. 2007. View Article : Google Scholar : PubMed/NCBI
8.	Miller AA, Case D, Harmon M, et al: Phase I study of lenalidomide in solid tumors. J Thorac Oncol. 2:445–449. 2007. View Article : Google Scholar : PubMed/NCBI
9.	Dahut WL, Aragon-Ching JB, Woo S, et al: Phase I study of oral lenalidomide in patients with refractory metastatic cancer. J Clin Pharmacol. 49:650–660. 2009. View Article : Google Scholar : PubMed/NCBI
10.	Bartlett JB, Tozer A, Stirling D and Zeldis JB: Recent clinical studies of the immunomodulatory drug (IMiD) lenalidomide. Br J Cancer. 93:613–619. 2005. View Article : Google Scholar : PubMed/NCBI
11.	Tohnya TM, Ng SS, Dahut WL, et al: A phase I study of oral CC-5013 (lenalidomide, Revlimid), a thalidomide derivative, in patients with refractory metastatic cancer. Clin Prostate Cancer. 2:241–243. 2004. View Article : Google Scholar : PubMed/NCBI
12.	Gupta D, Treon SP, Shima Y, et al: Adherence of multiple myeloma cells to bone marrow stromal cells up-regulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia. 15:1950–1961. 2001. View Article : Google Scholar
13.	Teo SK: Properties of thalidomide and its analogues: implications for anticancer therapy. AAPS J. 7:E14–E19. 2005. View Article : Google Scholar : PubMed/NCBI
14.	Corral LG, Haslett PA, Muller GW, et al: Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 163:380–386. 1999.PubMed/NCBI
15.	Dredge K, Marriott JB, Todryk SM, et al: Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1-type immunity. J Immunol. 168:4914–4919. 2002. View Article : Google Scholar : PubMed/NCBI
16.	Bartlett JB, Dredge K and Dalgleish AG: The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 4:314–322. 2004. View Article : Google Scholar : PubMed/NCBI
17.	Verhelle D, Corral LG, Wong K, et al: Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res. 67:746–755. 2007.PubMed/NCBI
18.	Kotla V, Goel S, Nischal S, et al: Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2:362009. View Article : Google Scholar : PubMed/NCBI
19.	Li S, Pal R, Monaghan SA, et al: IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM. Blood. 117:5157–5165. 2011.PubMed/NCBI
20.	Lopez-Girona A, Heintel D, Zhang LH, et al: Lenalidomide down-regulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol. 154:325–336. 2011. View Article : Google Scholar : PubMed/NCBI
21.	Puthalakath H and Strasser A: Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ. 9:505–512. 2002. View Article : Google Scholar : PubMed/NCBI
22.	Durchdewald M, Angel P and Hess J: The transcription factor Fos: a Janus-type regulator in health and disease. Histol Histopathol. 24:1451–1461. 2009.PubMed/NCBI
23.	Chhieng DC, Cangiarella JF, Zakowski MF, Goswami S, Cohen JM and Yee HT: Use of thyroid transcription factor 1, PE-10, and cytokeratins 7 and 20 in discriminating between primary lung carcinomas and metastatic lesions in fine-needle aspiration biopsy specimens. Cancer. 93:330–336. 2001. View Article : Google Scholar
24.	Tanaka H, Yanagisawa K, Shinjo K, et al: Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res. 67:6007–6011. 2007. View Article : Google Scholar : PubMed/NCBI
25.	Kwei KA, Kim YH, Girard L, et al: Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer. Oncogene. 27:3635–3640. 2008. View Article : Google Scholar : PubMed/NCBI
26.	Winslow MM, Dayton TL, Verhaak RG, et al: Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 473:101–104. 2011. View Article : Google Scholar : PubMed/NCBI