PubMed Health⌕ Search

Biomedical subjects

Waun Ki Hong

Publications and source records attributed to Waun Ki Hong.

At least 19 recordsLinked to original sources
PubMed2004

Effects of insulin-like growth factor binding protein-3 and farnesyltransferase inhibitor SCH66336 on Akt expression and apoptosis in non-small-cell lung cancer cells.

BACKGROUND: Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) induces apoptosis in non-small-cell lung cancer (NSCLC) cells in vitro and in vivo. However, Ras-mediated signaling pathways could develop resistance to apoptotic activities of IGFBP-3 in NSCLC cells. We thus evaluated the therapeutic potential of the combination of IGFBP-3 and SCH66336, a farnesyltransferase inhibitor that blocks Ras activation, in NSCLC cell lines. METHODS: The effects of the combination of adenoviral IGFBP-3 (Ad-IGFBP3) and SCH66336 on proliferation and apoptosis of NSCLC cell lines (H1299, H596, A549, H460, H358, H322, and H226B) were assessed in vitro and in vivo by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometry-based terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, western blot analyses, and an NSCLC xenograft tumor model. The specific effects of Ad-IGFBP 3 and SCH66336 on mitogen-activated protein kinase and Akt were assessed by using adenoviral vectors that express constitutively active MEK1 or constitutively active Akt. Synergy was assessed by median effect analysis. RESULTS: The combination of Ad-IGFBP3 and SCH66336 had synergistic antiproliferative effects in five cell lines (H1299, H596, A549, H460, and H322). Antiproliferative effects were accompanied by increased apoptosis in H460 cells in vitro. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. In H1299 tumor xenografts, Ad-IGFBP3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels. CONCLUSIONS: The combination of Ad-IGFBP3 and SCH66336 decreased Akt expression and increased apoptosis in NSCLC cells in vitro and in vivo. Simultaneous treatment with IGFBP-3 and SCH66336 may have the potential to be an effective therapeutic strategy in NSCLC.

Adenoviridae↗
PubMed2004

Value of p16INK4a and RASSF1A promoter hypermethylation in prognosis of patients with resectable non-small cell lung cancer.

The p16INK4a and RASSF1A are tumor suppressor genes frequently inactivated by de novo promoter hypermethylation in non-small cell lung cancer. We studied 119 patients with non-small cell lung cancer (70 stage I/II and 49 stage IIIA) who had undergone surgery with curative intent. The p16INK4a and RASSF1A promoter methylation statuses were determined by methylation-specific PCR. Statistical analyses, all two-sided, were performed to determine the prognostic effect of hypermethylation on various clinical parameters. Hypermethylation of the p16INK4a and RASSF1A promoters was found in 58 (49%) and 46 (39%) tumors, respectively, and 30 tumors (25%) exhibited hypermethylation of both gene promoters. In patients with stage I/II tumors, only p16INK4a promoter hypermethylation was associated with a poor 5-year overall survival rate (P=0.002). In patients with stage IIIA disease, however, RASSF1A promoter hypermethylation was a stronger predictor of a poor 5-year overall survival rate (P < 0.0001) than p16INK4a promoter hypermethylation. Among the 49 patients with stage IIIA tumors, 16 (89%) of the 18 patients whose tumors showed RASSF1A promoter hypermethylation died within 3 years after surgery, as compared with only 12 (39%) of the 31 patients whose tumors had no RASSF1A promoter hypermethylation (P < 0.0001). Multivariate analysis indicated that RASSF1A promoter hypermethylation was the stronger independent predictor for survival in patients with locally advanced non-small cell lung cancer. Our results indicate that p16INK4a promoter hypermethylation predicts a poor 5-year survival rates for patients with resectable non-small cell lung cancer, particularly for those with early stage tumors, whereas RASSF1A promoter hypermethylation is a profound prognostic predictor for patients with locally advanced non-small cell lung cancer, suggesting an important role of RASSF1A in non-small cell lung cancer progression.

Adult↗
PubMed2004

Mechanisms underlying lack of insulin-like growth factor-binding protein-3 expression in non-small-cell lung cancer.

Expression of insulin-like growth factor-binding protein-3, which (IGFBP-3) inhibits the proliferation of non-small-cell lung cancer (NSCLC) cells by inducing apoptosis, is lost in about half of stage I NSCLC cases. Since promoter methylation can silence gene expression, we investigated whether hypermethylation of the IGFBP-3 promoter is involved in loss of IGFBP-3 expression in NSCLC. We found the IGFBP-3 promoter to be methylated in seven of 13 NSCLC cell lines and in 16 of 23, seven of 9, eight of 11, and six of six tumor specimens from patients with stage I, II, III, and IV NSCLC, respectively. Methylation status correlated with IGFBP-3 mRNA and protein levels in a subset of NSCLC cell lines tested in our study. However, treatment with 5'-aza-2'-deoxycytidine (5'-aza-dC) restored IGFBP-3 expression in four of seven NSCLC cell lines with the methylated promoter, suggesting that multiple mechanisms regulate IGFBP-3 expression in NSCLC. Gel shift and chromatin immunoprecipitation assays showed that methylation of the Sp-1/Sp-3-binding element in the IGFBP-3 promoter influenced the binding of Sp-1, methyl-CpG-binding protein-2 (MeCP2), and histone deacetylase (HDAC). A luciferase construct expressing IGFBP-3 promoter in which the Sp-1/Sp-3 binding element was methylated showed significantly reduced transcriptional activity. The reduction in promoter activity was further suppressed by overexpression of MeCP2, which was rescued by 5'-aza-dC. Thus interference with Sp-1 transactivation by MeCP2 may contribute to the transcriptional defect of IGFBP-3 expression in NSCLC cells with methylated promoter.

Base Sequence↗
PubMed2004

Expression of hepatoma-derived growth factor is a strong prognostic predictor for patients with early-stage non-small-cell lung cancer.

PURPOSE: Hepatoma-derived growth factor (HDGF), which is unrelated to hepatocyte growth factor, can stimulate DNA synthesis and cell proliferation on entering the nucleus. We hypothesize that HDGF plays an important role in biologic behavior of early-stage non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Ninety-eight patients with pathologic stage I NSCLC who underwent curative surgery were studied. Immunohistochemistry was used to determine the expression level of HDGF in the tumor specimens. The intensity of the protein staining and percentage of stained tumor cells were used to determine a labeling index. Statistical analyses, all two-sided, were performed to determine the prognostic effect of HDGF expression levels on clinical parameters and outcomes. RESULTS: The mean +/- standard deviation HDGF labeling index in the 98 tumors was 185 +/- 41. Patients whose tumors had higher HDGF indexes (>/= 185) had a significantly poorer probability of overall survival at 5 years after surgery than did those with lower HDGF indexes (0.26 v 0.82; P <.0001). Similarly, the 5-year disease-specific and disease-free survival probabilities were lower in those with higher HDGF indexes (0.42 v 0.92, and 0.34 v 0.71; P <.0001 and P =.0008; respectively). Multivariate analysis indicated that HDGF level was an independent predictor of overall, disease-specific, and disease-free survivals. CONCLUSION: Overexpression of HDGF is common in early-stage NSCLC. The expression level in tumor cells is strongly correlated with poor overall, disease-specific, and disease-free survivals, suggesting HDGF may be a powerful prognostic marker for patients with early-stage NSCLC.

Adult↗
PubMed2004

Serum levels of insulin growth factor (IGF-I) and IGF-binding protein predict risk of second primary tumors in patients with head and neck cancer.

PURPOSE: Second primary tumors (SPTs) are a hallmark of head and neck squamous cell carcinomas (HNSCCs). Serum levels of insulin growth factors (IGFs) and their binding proteins (IGFBPs) have been associated with subsequent development of several epithelial cancers in prospective studies. EXPERIMENTAL DESIGN: To examine the role of IGFs in SPT development, we conducted a nested case-control study within a randomized, placebo-controlled chemoprevention trial in patients with early-stage HNSCC. We compared prediagnostic serum IGF-I and IGFBP-3 levels in 80 patients who subsequently developed SPTs and 173 controls (patients without SPTs) matched to the cases on age (+/-5 years), sex, ethnicity, year of randomization, and length of follow-up. RESULTS: The cases exhibited significantly higher levels of IGF-I and IGFBP-3 than did the controls (P = 0.001 and 0.019, respectively). Elevated IGF-I levels were associated with a 3.66-fold significantly increased risk of SPT. Lower and higher IGFBP-3 levels were associated with a 2.22- and 7.12-fold significant increased risk, respectively. The median SPT-free time was significantly shorter in patients with higher IGF-I levels than in patients with lower IGF-I levels (P < 0.0001). A similar trend was observed for IGFBP-3 (P = 0.002). Moreover, in the Cox proportional hazards model, higher IGF-I levels were significantly associated with increased risk of SPT with a hazard ratio of 2.78. Patients with the lower and higher IGFBP-3 levels also exhibited significantly increased risks with hazard ratios of 1.65 and 2.17, respectively. CONCLUSIONS: This is the first study demonstrating that higher IGF-I levels, and lower and higher IGFBP-3 levels are risk factors for SPT development. Thus, measuring serum IGF-I and IGFBP-3 levels may be useful markers in assessing the risk of second tumors in patients successfully treated for their index cancer.

Adult↗
PubMed2004

Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors.

PURPOSE: To establish the maximum tolerated dose of lonafarnib, a novel farnesyltransferase inhibitor, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, dose-limiting toxicity, and pharmacokinetics of this combination regimen. EXPERIMENTAL DESIGN: In a Phase I trial, lonafarnib was administered p.o., twice daily (b.i.d.) on continuously scheduled doses of 100 mg, 125 mg, and 150 mg in combination with i.v. paclitaxel at doses of 135 mg/m(2) or 175 mg/m(2) administered over 3 h on day 8 of every 21-day cycle. Plasma paclitaxel and lonafarnib concentrations were collected at selected time points from each patient. RESULTS: Twenty-four patients were enrolled; 21 patients were evaluable. The principal grade 3/4 toxicity was diarrhea (5 of 21 patients), which was most likely due to lonafarnib. dose-limiting toxicities included grade 3 hyperbilirubinemia at dose level 3 (100 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); grade 4 diarrhea and grade 3 peripheral neuropathy at dose level 3A (125 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); and grade 4 neutropenia with fever and grade 4 diarrhea at level 4 (150 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel). The maximum tolerated dose established by the continual reassessment method was lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m(2). Paclitaxel appeared to have no effect on the pharmacokinetics of lonafarnib. The median duration of therapy was eight cycles, including seven cycles with paclitaxel. Six of 15 previously treated patients had a durable partial response, including 3 patients who had previous taxane therapy. Notably, two of five patients with taxane-resistant metastatic non-small cell lung cancer had partial responses. CONCLUSIONS: When combined with paclitaxel, the recommended dose of lonafarnib for Phase II trials is 100 mg p.o. twice daily with 175 mg/m(2) of paclitaxel i.v. every 3 weeks. Additional studies of lonafarnib in combination regimens appear warranted, particularly in patients with non-small cell lung cancer.

Adult↗
PubMed2004

Deguelin-induced inhibition of cyclooxygenase-2 expression in human bronchial epithelial cells.

The increased expression of cyclooxygenase (COX)-2 significantly enhances carcinogenesis and inflammatory reactions, and its regulation may be a reasonable target for cancer chemoprevention. We demonstrated previously that deguelin inhibits proliferation of premalignant human bronchial epithelial (HBE) cells, such as 1799 cells and squamous HBE cells, by regulating phosphatidylinositol-3-kinase Akt activity, which is involved in COX-2 expression. We sought to determine the effect of deguelin on COX-2 expression in squamous HBE cells. Deguelin strongly inhibited COX-2 expression in squamous HBE cells, without affecting the COX-1 protein level. Deguelin inhibited proliferation of a variety of non-small cell lung carcinoma (NSCLC) cell lines through apoptosis and induced Bax expression in the H322 NSCLC and squamous HBE cells. Deguelin treatment did not affect Bcl-2 protein levels but increased expression levels of the proapoptotic protein p53 and the cyclin-dependent kinase inhibitors p21 and p27 in the squamous HBE cells. The sensitivity of the squamous HBE and NSCLC cells to deguelin and the inhibitory effects of deguelin on COX-2 expression in the squamous HBE cells indicate that regulation of COX-2 expression is involved in the chemopreventive action of deguelin in lung cancer.

Apoptosis↗
PubMed2004

The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells.

PURPOSE: Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including those of the head and neck and breast. Accordingly, agents such as the EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (Iressa) are promising, biologically based treatments that are in various stages of preclinical and clinical development. The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced cell survival; this study explored the effect of ZD1839 on the stimulation of c-Src and p21-activated kinase 1 (Pak1), which are vital for transformation, directional motility, and cell survival of cancer cells. EXPERIMENTAL DESIGN: We examined the effect of ZD1839 on biochemical and functional assays indicative of directional motility and cell survival, using human head and neck squamous cancer cells and breast cancer cells. RESULTS: ZD1839 effectively inhibited c-Src activation and Pak1 activity in exponentially growing cancer cells. In addition, ZD1839 suppressed EGF-induced stimulation of EGFR autophosphorylation on Y1086 and Grb2-binding Y1068 sites, c-Src phosphorylation on Y215, and Pak1 activity. ZD1839 also blocked EGF-induced cytoskeleton remodeling, redistribution of activated EGFR, and in vitro invasiveness of cancer cells. CONCLUSIONS: These studies suggest that the EGFR-TKI ZD1839 may cause potent inhibition of the Pak1 and c-Src pathways and, therefore, have potential to affect the invasiveness of human cancer cells deregulated in these growth factor receptor pathways.

Antineoplastic Agents↗
PubMed2004

Antisense oligonucleotides directed at the bcl-xl gene product augment chemotherapy response in mesothelioma.

OBJECTIVE: Malignant pleural mesothelioma (MPM) is resistant to both conventional chemotherapy and apoptosis. The bcl-2 family proteins are major determinants of apoptotic homeostasis. MPM lines and tumors routinely overexpress the anti-apoptotic protein BCL-XL. We have previously shown that antisense inhibition of BCL-XL in MPM cells leads to apoptosis. We sought to determine whether antisense oligonucleotides directed at the bcl-xl gene product would augment response to a conventional chemotherapeutic agent in human mesothelioma cell lines. METHODS: The human MPM cell lines REN and I-45 were exposed to two bcl-xl antisense oligonucleotides (15999, 16009) and one sense oligonucleotide (113529) construct at varying doses, followed by IC(50) cisplatin. Cellular viability was assessed by a calorimetric assay, and apoptosis was evaluated by Hoechst staining, Annexin V staining, and sub-G(1) fluorescence-activated cell sorter analysis. Western blot analysis of BCL-2 family proteins was performed following single agent and combined treatment. Isobologram mathematical analysis was used to determine whether or not combination therapies were additive or synergistic. RESULTS: Cell viability was most affected with the 15999 antisense oligonucleotides plus IC(50) cisplatin combination (70% of I-45 and 90% of REN cells killed), and apoptosis was markedly increased with this combination by all measures. Western blot demonstrated 15999 antisense oligonucleotides construct down-regulation of BCL-XL, but no further effect on expression of BCL-2 proteins with cisplatin. Isobologram analysis demonstrated 15999 + cisplatin synergistic effect. CONCLUSIONS: Exposure of human MPM cells to bcl-xl antisense oligonucleotides sensitizes human mesothelioma cells to the conventional chemotherapeutic agent cisplatin. Similar approaches using a combination of molecular and conventional treatment may have clinical utility for this tumor.

Apoptosis↗
PubMed2004

A novel C/T polymorphism in the core promoter of human de novo cytosine DNA methyltransferase 3B6 is associated with prognosis in head and neck cancer.

New biomarkers for head and neck squamous cell carcinoma (HNSCC) patients are being sought to help predict disease outcome, guide treatment, and develop new treatments. In the present study, the association between a novel functional C/T polymorphism in the core promoter of cytosine DNA methyltransferase (DNMT) 3B6 and overall survival of HNSCC patients was investigated. Genomic DNA was extracted from tumor tissue and leukocytes from each HNSCC patient. We used the PCR-restriction fragment length polymorphism (PCR-RFLP) assay to determine the DNMT3B genotype. Kaplan-Meier product-limit method and univariate/multivariate Cox proportional hazard models were used to correlate DNMT3B genotype with overall survival of HNSCC patients who underwent surgical resection. There was a marked association between DNMT3B C/T polymorphism and overall survival of HNSCC patients (P=0.004). The homozygotes (CC-genotype and TT-genotype) survived significantly longer than the heterozygotes (CT-type). The multivariate Cox proportional hazard modeling showed that HNSCC patients with CT-genotype had a hazard ratio of 4.829 over patients with CC-genotype or TT-genotype. A DNMT3B C/T polymorphism has been correlated with survival differences in HNSCC patients. If validated in larger studies, this polymorphism might be used to identify deleterious patterns of gene silencing by methylation in HNSCC.

Adult↗
PubMed2003

Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice.

PURPOSE: This study was conducted to develop biologically relevant animal models of human lung cancer that are reproducible, inexpensive, and easy to perform. EXPERIMENTAL DESIGN: Human lung adenocarcinoma (PC14PE6), bronchioloalveolar carcinoma (NCI-H358), squamous cell carcinoma (NCI-H226), poorly differentiated non-small cell lung cancer (NCI-H1299 and A549), or small cell lung cancer (NCI-H69) cells in Matrigel were injected percutaneously into the left lungs of nude mice. The growth pattern of the different lung cancer tumors was studied. For PC14PE6 and NCI-H358, the growth pattern in the subcutis and the response to paclitaxel were also studied. RESULTS: As is observed for human primary lung cancer, tumors formed from a single focus of disease and progressed to a widespread and fatal thoracic process characterized by diffuse dissemination of lung cancer in both lungs and metastasis to intra- and extrathoracic lymph nodes. When the lung cancer cell lines were implanted s.c., systemic therapy with paclitaxel induced tumor regression. However, only a limited therapeutic response to paclitaxel was observed when the same cells were implanted orthotopically into the lung. Immunohistochemical analysis of tumor tissue revealed increased expression of the proangiogenic factors interleukin 8, basic fibroblast growth factor, and vascular endothelial growth factor/vascular permeability factor. CONCLUSIONS: Our orthotopic models of human lung cancer confirm the "seed and soil" concept and likely provide more clinically relevant systems for the study of both non-small cell lung cancer and small cell lung cancer biology, and for characterizing novel therapeutic strategies.

Animals↗
PubMed2003

An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia.

PURPOSE: Dysplastic lesions of the oral epithelium are known precursors of oral cancer. A significant proportion of oral dysplastic lesions have functional defects in p53 response pathways. The ONYX-015 adenovirus is selectively cytotoxic to cells carrying defects in p53-dependent signaling pathways. The current study sought to establish the feasibility and activity of ONYX-015 administered topically as a mouthwash to patients with clinically apparent and histologically dysplastic lesions of the oral mucosa. PATIENTS AND METHODS: A total of 22 patients (19 assessable patients) were enrolled onto the study. ONYX-015 was administered on three different schedules to consecutive cohorts. Biopsies of the involved mucosa were performed to evaluate histologic response and changes in expression of putative markers of malignant potential, including p53, cyclin D1, and Ki-67. Serology was performed to measure antiadenoviral titers. RESULTS: Histologic resolution of dysplasia was seen in seven (37%) of 19 patients, and the grade of dysplasia improved in one additional patient. The majority of responses were transient. No toxicity greater than grade 2 (febrile episode in one patient) was observed. Only one of seven patients demonstrated an increase in circulating antiadenoviral antibody titer while on therapy. Although responding and resistant lesions had similar mean p53 staining at baseline, histologic response correlated with a decrease in p53 positivity over time. Significant changes in cyclin D1 or Ki-67 were not observed. Viral replication was confirmed in two of three lesions examined. CONCLUSION: This novel approach to cancer prevention is tolerable, feasible, and has demonstrable activity.

Adenoviridae↗
PubMed2003

Enolase-alpha is frequently down-regulated in non-small cell lung cancer and predicts aggressive biological behavior.

PURPOSE: Enolase-alpha is a cytoplasmic glycolytic enzyme important in the formation of phosphoenolpyruvate. Enolase-alpha and c-myc binding protein (MBP-1) originate from a single gene through alternative use of translational starting sites. Both enolase-alpha and MBP-1 can bind to the P2 element in the c-myc promoter and compete with TATA-box binding protein (TBP) to suppress transcription of c-myc. EXPERIMENTAL DESIGN: To determine a potential role of enolase-alpha in vivo, we analyzed enolase-alpha expression in non-small cell lung cancer (NSCLC) tissues from 46 patients by Western blotting and immunohistochemical analysis. RESULTS: Twelve (26%) of the 46 tumors showed a significantly reduced enolase-alpha expression. Although no statistically significant association was observed between the down-regulation of enolase-alpha and pathological stage, tumor histology, or differentiation, the patients whose tumors showed reduced enolase-alpha expression had a significantly poorer overall survival compared with those without down-regulation of this molecule (P = 0.0398). CONCLUSIONS: Our results indicate down-regulation of enolase-alpha is common in NSCLC and may play an important role in lung tumorigenesis.

Aged↗
PubMed2003

Telomere dysfunction: a potential cancer predisposition factor.

BACKGROUND: Genetic instability associated with telomere dysfunction (i.e., short telomeres) is an early event in tumorigenesis. We investigated the association between telomere length and cancer risk in four ongoing case-control studies. METHODS: All studies had equal numbers of case patients and matched control subjects (92 for head and neck cancer, 135 for bladder cancer, 54 for lung cancer, and 32 for renal cell carcinoma). Telomere length was measured in peripheral blood lymphocytes from study participants. Genetic instability was assessed with the comet assay. Patient and disease characteristics were collected and analyzed for associations with risk for these cancers. All statistical tests were two-sided. RESULTS: Telomeres were statistically significantly shorter in patients with head and neck cancer (6.5 kilobases [kb]) than in control subjects (7.4 kb) (difference = 0.9 kb, 95% confidence interval [CI] = 0.5 to 1.2 kb; P<.001). Nine percent of patients with head and neck cancer were in the longest quartile of telomere length, whereas 59% were in the shortest quartile. Similar patterns were observed for lung, renal cell, and bladder cancer. When subjects were categorized into telomere length quartiles defined by the distribution in control subjects, the following inverse relationship between telomere length and cancer risk was observed: adjusted odds ratios [ORs] for decreasing quartiles = 0.84 (95% CI = 0.36 to 1.97), 1.77 (95% CI = 0.72 to 4.36), and 5.11 (95% CI = 1.90 to 13.77). In stratified analysis, we found a suggestive greater-than-additive interaction between smoking status and telomere length: for ever smokers with short telomeres, OR = 25.05 (95% CI = 6.91 to 90.73); for never smokers with short telomeres, OR = 6.18 (95% CI = 1.72 to 22.13); and for ever smokers with long telomeres, OR = 6.49 (95% CI = 1.54 to 27.38). Telomere length was statistically significantly and inversely associated with baseline and mutagen-induced genetic instability. CONCLUSION: Short telomeres appear to be associated with increased risks for human bladder, head and neck, lung, and renal cell cancers.

Adult↗
PubMed2003

Implication of protein kinase B/Akt and Bcl-2/Bcl-XL suppression by the farnesyl transferase inhibitor SCH66336 in apoptosis induction in squamous carcinoma cells.

The farnesyltransferase inhibitor SCH66336 exhibits antitumor activity in vitro and in vivo; however, its mechanism of action is still unresolved. We found that SCH66336 suppressed growth and induced apoptosis of human head and neck squamous carcinoma cells (HNSCC). SCH66336 suppressed protein kinase B/Akt activity as well as the phosphorylation of the Akt substrates glycogen synthase kinase (GSK)-3 beta, forkhead transcription factor, and BAD. Infection of SqCC/Y1 cells with an adenovirus that contained a constitutively active form of Akt rescued cells from SCH66336-induced apoptosis. These results suggest that SCH66336 is a potent apoptosis inducer in HNSCC cells and that it may act by suppressing the Akt pathway.

Alkyl and Aryl Transferases↗
PubMed2003

The synthetic heteroarotinoid SHetA2 induces apoptosis in squamous carcinoma cells through a receptor-independent and mitochondria-dependent pathway.

Retinoids that regulate cell growth, differentiation, and apoptosis have shown promising results in preclinical studies and in a few clinical trials of cancer chemoprevention and therapy. However, the clinical use of retinoids is limited by resistance of certain malignant cells to their antitumor effects and by side effects. To identify more potent retinoids, we examined the effects of heteroarotinoids (Hets), new synthetic retinoids with reduced toxicity, on the growth of human head and neck squamous cell carcinoma (HNSCC) lines. Six Hets with different retinoic acid receptor activation potentials were found to exhibit distinct efficacies. The most potent among the Hets examined, SHetA2, [[(4-nitrophenyl)amino][2,2,4,4-tetramethyl thiochroman-6-yl)amino] methane-1-thione], was more effective than either all-trans- or 9-cis-RA. The growth of UMSCC38, the most sensitive among the eight HNSCC cell lines examined, was suppressed by ShetA2 in a dose- and time-dependent fashion. SHetA2-induced apoptosis in UMSCC38 cells was comparable with N-(4-hydroxyphenyl)retinamide (4HPR). Reactive oxygen species (ROS) generation in the UMSCC38 cells was increased by SHetA2, and this effect was suppressed by the antioxidant butylated hydroxyanisol, which also suppressed SHetA2-induced apoptosis. SHetA2 suppressed mitochondrial permeability transition and enhanced cytochrome c release from mitochondria. Both of these effects were prevented by cyclosporin A, which also decreased SHetA2-induced apoptosis. SHetA2 increased caspase-3-like activity, and a caspase-3 inhibitor diminished SHetA2-induced apoptosis. Several retinoid receptor antagonists failed to prevent apoptosis induction by SHetA2. These results demonstrate that SHetA2 is a potent, receptor-independent, apoptosis inducer that acts on the mitochondria in HNSCC cells. Further investigation of the potential of SHetA2 in prevention and therapy of HNSCC is warranted also because of much lower toxicities compared with receptor active retinoids.

Apoptosis↗
PubMed2003

Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells.

BACKGROUND: Because lung cancer is the leading cause of cancer-related death, new approaches for preventing and controlling the disease are needed. Chemoprevention approaches are both feasible and effective. We evaluated the potential of deguelin, a natural plant product, as a lung cancer chemopreventive agent and investigated its mechanism of action. METHODS: The effects of deguelin on proliferation and apoptosis of normal, premalignant, and malignant human bronchial epithelial (HBE) cells were assessed by using the MTT assay, a flow cytometry-based TUNEL assay, and western blot analyses. The effects of deguelin on the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways were assessed by western blot analyses and with adenoviral vectors that expressed constitutively active Akt. RESULTS: Deguelin treatment in vitro at doses attainable in vivo inhibited the growth of and induced apoptosis of premalignant and malignant HBE cells but had minimal effects on normal HBE cells. Levels of phosphorylated Akt (pAkt) were higher in premalignant HBE cells than in normal HBE cells. In premalignant HBE cells, deguelin inhibited PI3K activity and reduced pAkt levels and activity but had mimimal effects on the MAPK pathway. Although overexpression of a constitutively active Akt in premalignant and malignant HBE cells had no effect on growth inhibition mediated by N-(4-hydroxyphenyl)retinamide (4-HPR), a novel chemopreventive retinoid, it blocked deguelin-induced growth arrest and apoptosis. CONCLUSIONS: The ability of deguelin to inhibit PI3K/Akt-mediated signaling pathways may contribute to the potency and specificity of this pro-apoptotic drug. Because both premalignant and malignant HBE cells are more sensitive to deguelin than normal HBE cells, deguelin may have potential as both a chemopreventive agent for early stages of lung carcinogenesis and a therapeutic agent against lung cancer.

Antineoplastic Agents↗