Molecular targets of the chemopreventive agent 1,4-phenylenebis (methylene)-selenocyanate in human non-small cell lung cancer.
Clinical chemoprevention trials of lung cancer have been somewhat disappointing and the development of highly effective chemopreventive agents is urgently needed. We previously showed that the organoselenium 1,4-phenylenebis(methylene)selenocyanate (p-XSC) is a potent chemopreventive agent in numerous preclinical animal models including a lung tumor model that employs carcinogens found in tobacco smoke. The goal of this study is to define molecular targets that will be highly promising in the design of future chemoprevention trials of non-small cell lung cancer (NSCLC), which is by far the most common type of lung cancer cases. In the present investigation, we showed that p-XSC at several doses (2.5, 5, 10 and 20 microM) including physiological levels (2.5-5.0 microM) of selenium is capable of inhibiting cell growth in a dose-dependent manner and inducing apoptosis in three NSCLC cells (NCI-H460, NCI-1299 and A549). To clarify the mechanism involved at the molecular level, we focused only on NCI-460 cells and examined the effects of p-XSC on markers that are known to be critical in the development of NSCLC. Using western blot analysis, we showed that p-XSC reduced the expression of cyclooxygenase-2 (COX-2) and phospholipase A2 (PLA2); although p-XSC inhibited both Akt and p-Akt but its effect was not significant. Using cDNA microarray approach (3800 genes per array) we found that p-XSC upregulates 22 genes by > or = 2-fold while downregulates 13 genes by < or = 0.5-fold; these altered genes include transcriptional factors, growth factors and those involved in xenobiotic metabolism as well as pro- and anti-apoptotic genes. Expression of selected genes was confirmed by RT-PCR; p-XSC reduced the levels of COX-2, PLA2, NF-kappaB and Cyclin D1 but enhanced the levels of glutathione peroxidase-5. Collectively, the results of this study showed that p-XSC alters several molecular markers in a manner that can account for its inhibitory effect of cell growth and induction of apoptosis; therefore, p-XSC may be considered a promising candidate for clinical chemoprevention of NSCLC.
El-Bayoumy
Karam
K
Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Kelbayoumy@aol.com
Das
Arunangshu
A
Narayanan
Bhagavathi
B
Narayanan
Narayanan
N
Fiala
Emerich S
ES
Desai
Dhimant
D
Rao
Chinthalapally V
CV
Amin
Shantu
S
Sinha
Raghu
R
D016824:Antigens, Human Platelet / Q000187:drug effects; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D019938:Cyclin D1 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008565:Membrane Proteins / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D051058:Oncogene Protein v-akt / Q000187:drug effects; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016824:Antigens, Human Platelet; D000970:Antineoplastic Agents; D008565:Membrane Proteins; D016328:NF-kappa B; D016566:Organoselenium Compounds; C083451:human platelet antigen 1b; D019938:Cyclin D1; C074153:1,4-phenylenebis(methylene)selenocyanate; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051058:Oncogene Protein v-akt