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Anticancer Effects (anticancer + effects)

Distribution by Scientific Domains

Medical Sciences	70%
Life Sciences	23%

Selected Abstracts

Anticancer effects of zoledronic acid against human osteosarcoma cells

JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2006
B. Kubista
Abstract Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N,=,9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source]

Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib ("Iressa")-sensitive and resistant xenograft models

CANCER SCIENCE, Issue 12 2004
Fumiko Taguchi
ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor (VEGF) receptor-2 (KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 has been shown to inhibit angiogenesis and tumor growth in a range of tumor models. Gefitinib ("Iressa") is an selective EGFR tyrosine kinase inhibitor (TKI) that blocks signal transduction pathways. We examined the antitumor activity of ZD6474 in the gefitinib-sensitive lung adenocarcinoma cell line, PC-9, and a gefitinib-resistant variant (PC-9/ZD). PC-9/ZD cells showed cross-resistance to ZD6474 in an in vitro dye formation assay. In addition, ZD6474 showed dose-dependent inhibition of EGFR phosphorylation in PC-9 cells, but inhibition was only partial in PC-9/ZD cells. ZD6474-mediated inhibition of tyrosine residue phosphorylation (Tyr992 and Tyr1045) on EGFR was greater in PC-9 cells than in PC-9/ZD cells. These findings suggest that the inhibition of EGFR phosphorylation by ZD6474 can contribute a significant, direct growth-inhibitory effect in tumor cell lines dependent on EGFR signaling for growth and/or survival. The effect of ZD6474 (12.5,50 mg/kg/day p.o. for 21 days) on the growth of PC-9 and PC-9/ZD tumor xenografts in athymic mice was also investigated. The greatest effect was seen in gefitinib-sensitive PC-9 tumors, where ZD6474 treatment (>12.5 mg/kg/day) resulted in tumor regression. Dose-dependent growth inhibition, but not tumor regression, was seen in ZD6474-treated PC-9/ZD tumors. These studies demonstrate that the additional EGFR TKI activity may contribute significantly to the anti-tumor efficacy of ZD6474, in particular in those tumors that are dependent on continued EGFR-signaling for proliferation or survival. In addition, these results provide a preclinical rationale for further investigation of ZD6474 as a potential treatment option for both EGFR-TKI-sensitive and EGFR-TKI-resistant tumors. [source]

Thiazolidinediones and the preservation of ,-cell function, cellular proliferation and apoptosis

DIABETES OBESITY & METABOLISM, Issue 8 2008
Michael Decker
The thiazolidinediones (TZDs) or glitazones are pharmaceutical agents that have profound effects on energy expenditure and conservation. They also exert significant anti-inflammatory effects and influence cell proliferation and cell death. The drugs are primarily used in clinical practice in the treatment of patients with type 2 diabetes mellitus, a disorder of insulin resistance that occurs when the pancreatic ,-cells are unable to produce adequate amounts of insulin to maintain euglycaemia. Loss of pancreatic ,-cell function in type 2 diabetes is progressive and often precedes overt diabetes by 10 years or more, as was shown by the United Kingdom Prospective Diabetes Study. Any therapeutic or preventive approach that would limit or reverse loss of ,-cell function in diabetes would have profound effects on the morbidity associated with this widespread disease. Evidence suggesting a potential role of TZDs in preserving ,-cell function in type 2 diabetes as well as the ability of these agents to exert anti-inflammatory and proapoptotic anticancer effects, and their ability to promote cellular proliferation in various organs is reviewed. [source]

EGF receptor in relation to tumor development: molecular basis of responsiveness of cancer cells to EGFR-targeting tyrosine kinase inhibitors

FEBS JOURNAL, Issue 2 2010
Kenji Takeuchi
The function of the epidermal growth factor receptor (EGFR) is dysregulated in various types of malignancy as a result of gene amplification, mutations, or abnormally increased ligand production. Therefore, the tyrosine kinase activity of the EGFR is a promising therapeutic target. EGFR tyrosine kinase inhibitors, such as gefitinib (Iressa), show evident anticancer effects in patients with non-small cell lung cancer. The induction of apoptosis has been considered to be the major mechanism for these gefitinib-mediated anticancer effects. Lung cancer cells harboring mutant EGFRs become dependent on them for their survival and, consequently, undergo apoptosis following the inhibition of EGFR tyrosine kinase by gefitinib. Gefitinib has been shown to inhibit cell survival and growth signaling pathways such as the extracellular signal-regulated kinase 1/2 pathway and the Akt pathway, as a consequence of the inactivation of EGFR. However, the precise downstream signaling molecules of extracellular signal-regulated kinase 1/2 and Akt have not yet been elucidated. In this minireview we have highlighted the effect of tyrosine kinase inhibitors on members of the Bcl-2 family of proteins, which are downstream signaling molecules and serve as the determinants that control apoptosis. We also discuss tyrosine kinase inhibitor-induced apoptosis via c-Jun NH2 -terminal kinase and p38 mitogen-activated protein kinase. [source]

Loco-regional treatment of hepatocellular carcinoma,

HEPATOLOGY, Issue 2 2010
Riccardo Lencioni
Loco-regional treatments play a key role in the management of hepatocellular carcinoma (HCC). Image-guided tumor ablation is recommended in patients with early-stage HCC when surgical options are precluded. Radiofrequency ablation has shown superior anticancer effects and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials, and is currently established as the standard method for local tumor treatment. Novel thermal and nonthermal techniques for tumor ablation,including microwave ablation, irreversible electroporation, and light-activated drug therapy,seem to have potential to overcome the limitations of radiofrequency ablation and warrant further clinical investigation. Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with asymptomatic, noninvasive multinodular tumors at the intermediate stage. The recent introduction of embolic microspheres that have the ability to release the drug in a controlled and sustained fashion has been shown to significantly increase safety and efficacy of TACE with respect to conventional, lipiodol-based regimens. The available data for radioembolization with yttrium-90 suggests that this is a potential new option for patients with HCC, which should be investigated in the setting of randomized controlled trials. Despite the advances and refinements in loco-regional approaches, the long-term survival outcomes of patients managed with interventional techniques are not fully satisfactory, mainly because of the high rates of tumor recurrence. The recent addition of molecular targeted drugs with antiangiogenic and antiproliferative properties to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between loco-regional and systemic treatments. The outcomes of these trials are eagerly awaited, because they have the potential to revolutionize the treatment of HCC. (HEPATOLOGY 2010;) [source]

Inhibition of 13-cis retinoic acid-induced gene expression of homeobox B7 by thalidomide

INTERNATIONAL JOURNAL OF CANCER, Issue 6 2007
an Milanovi
Abstract Thalidomide and 13-cis retinoic acid (RA) show anticancer effects as sole agents or in combination with other drugs. However, induction of homeobox (HOX) gene expression by 13-cis RA may contribute to tumor progression thereby potentially limiting its efficacy. The purpose was to test if thalidomide can inhibit 13-cis RA-induced HOXB7 expression and whether thalidomide may enhance the antiproliferative effect of 13-cis RA in U343MG glioblastoma cells. Quantitative real-time PCR showed significant inhibition of 13-cis RA-induced HOXB7 expression by thalidomide with IC50 , 0.1,0.2 ,g/ml when given simultaneously with 13-cis RA but not when administered 18h later (p < 0.0001). 13-cis RA alone inhibited proliferation and colony formation in a concentration-dependent manner whereas growth inhibition by thalidomide alone at 5,100 ,g/ml was constant at 80,90% of controls. At 10% serum concentration, growth inhibition by a combination of the 2 drugs was additive but at 1% serum, growth inhibition was synergistic. It is concluded that thalidomide inhibits the RA-induced HOXB7 expression in glioblastoma cells and that 13-cis RA/thalidomide combinations can in principle enhance cytotoxicity. The improved cell kill induced by thalidomide is attributed to downregulation of growth stimulatory factors induced by 13-cis RA. Implications for the modus operandi of thalidomide in embryogenesis are noted. © 2007 Wiley-Liss, Inc. [source]

Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model

INTERNATIONAL JOURNAL OF CANCER, Issue 1 2005
Eunyoung Chun
Abstract Inhibition of angiogenesis is emerging as a promising strategy for the treatment of cancer. In our study reported here, the effects of 4 highly potent methionine aminopeptidase 2 (MetAP2) inhibitors, IDR-803, IDR-804, IDR-805 and CKD-732 (designed by structure-based molecular modeling), on angiogenesis and tumor growth were assessed. Concentrations of these inhibitors as low as 2.5 nM were able to inhibit the growth of human umbilical vein endothelial cells (HUVEC) by as much as 50%, arresting growth in the G1 stage of mitosis. An intracellular accumulation of p21WAF1/Cip1 protein was also observed. Furthermore, at higher concentrations (25 nM) of these 4 MetAP2 inhibitors, a significant induction of apoptosis was apparent in the same HUVEC cultures. As a result of these findings, the possible anticancer effects of these inhibitors were examined, utilizing the SNU-398 hepatoma cell line. Interestingly, pretreatment with these inhibitors led to an increased number of apoptotic cells of up to 60% or more, compared to untreated controls. Moreover, utilizing an in vivo xenografted murine model, these inhibitors suppressed the growth of engrafted tumor. In conclusion, these 4 inhibitory compounds potently exert an antiangiogenic effect to inhibit the growth of cancers in vivo and could potentially be useful for the treatment of a variety of cancers. © 2004 Wiley-Liss, Inc. [source]

Galactosyl derivative of N, -nitro- L -arginine: Study of antiproliferative activity on human thyroid follicular carcinoma cells

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2009
Daniela Melisi
The methyl ester prodrug of N, -nitro- L -arginine (L -NAME) has been reported to exert anticancer effects against several human tumors, including thyroid carcinoma, by inhibiting nitric oxide synthase (NOS). However, chronic administration of L -NAME has often led to adverse events causing cardiovascular alterations due to its potential toxic effect. Here we report for the first time the synthesis of the galactosyl ester prodrug of N, -nitro- L -arginine, NAGAL, a prodrug capable of inhibiting NOS more efficiently and with fewer adverse events than its parent drug. For this purpose RO82-W-1, a thyroid cell line derived from human follicular carcinoma, was used. MTT test results showed that NAGAL affected cell viability to a significantly greater extent than did L -NAME. Moreover, fluorescence activated cell sorter (FACS) analyses revealed that NAGAL, compared to L -NAME, was able to reduce nitric oxide (NO) production as well as increase the percentage of apoptotic thyreocytes. Western blot further confirmed the reduction in NOS-II expression by NAGAL. Finally, by using the LC,MS technique, we found that NAGAL elicited a higher increase in N, -nitro- L -arginine (NA) concentration than did L -NAME. Thus, this study suggests that NAGAL could be considered a potential therapeutic tool for those pathologies involving an overproduction of NO, including thyroid carcinoma. J. Cell. Physiol. 221: 440,447, 2009. © 2009 Wiley-Liss, Inc. [source]

Cimetidine inhibits epidermal growth factor-induced cell signaling

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2007
Tatsuya Fujikawa
Abstract Background:, Cimetidine, a histamine-2 (H2) receptor antagonist, has been demonstrated to have anticancer effects on colorectal cancer, melanoma and renal cell carcinoma. In the current study, we clarified that cimetidine inhibits both epidermal growth factor (EGF)-induced cell proliferation and migration in hepatocellular carcinoma (HCC) cell lines. Method:, HCC cell lines (Hep3B, HLF, SK-Hep-1, JHH-2, PLC/PRF/5 and HLE) were used and cell proliferation was assessed by [3H]-thymidine incorporation assay. Cell migration was measured by in vitro cell migration assay. Biological effects of cimetidine were assessed with human EGF receptor (EGFR)-expressing mouse fibroblast cells (NR6-WT). The autophosphorylation of EGFR and the activation of other downstream effectors were analyzed by immunoprecipitation and immunoblotting. The concentration of intracellular cyclic AMP (cAMP) was measured by competitive enzyme immunoassay. Results:, Cimetidine inhibited both EGF-induced cell proliferation and migration in Hep3B, HLF, SK-Hep-1 and JHH-2, while cimetidine did not affect EGF-induced cell proliferation and migration in PLC/PRF/5 and HLE. Cimetidine was revealed to disrupt the EGF-induced autophosphorylation of EGFR and its downstream effectors, mitogen activated protein kinases and phospholipase C-,. To define the molecular basis of this negative regulation, we identified that cimetidine significantly decreased intracellular cAMP levels and that decrement of cAMP inhibited autophosphorylation of EGFR. The cell permeable cAMP analog, CPT-cAMPS reversed the cimetidine-induced inhibition of EGF-induced cell proliferation and cell migration by restoring autophosphorylation of EGFR. Conclusion:, Cimetidine inhibited EGF-induced cell proliferation and migration in HCC cell lines by decreasing the concentration of intracellular cAMP levels. Cimetidine may be a candidate chemopreventive agent for HCC. [source]

Anticancer effects of zoledronic acid against human osteosarcoma cells

Polyporenic acid C induces caspase-8-mediated apoptosis in human lung cancer A549 cells

MOLECULAR CARCINOGENESIS, Issue 6 2009
Hui Ling
Abstract Lung cancer continues to be the leading cause of cancer-related mortality worldwide. This warrants the search for new and effective agents against lung cancer. We and others have recently shown that lanostane-type triterpenoids isolated from the fungal species Poria cocos (P. cocos) can inhibit cancer growth. However, the mechanisms responsible for the anticancer effects of these triterpenoids remain unclear. In this study, we investigated the effect of polyporenic acid C (PPAC), a lanostane-type triterpenoid from P. cocos, on the growth of A549 nonsmall cell lung cancer cells (NSCLC). The results demonstrate that PPAC significantly reduced cell proliferation via induction of apoptosis as evidenced by sub-G1 analysis, annexin V-FITC staining, and increase in cleavage of procaspase-8, -3, and poly(ADP-ribose)-polymerase (PARP). However, unlike our previously reported lanostane-type triterpenoid, pachymic acid, treatment of cells with PPAC was not accompanied by disruption of mitochondrial membrane potential and increase in cleavage of procaspase-9. Further, PPC-induced apoptosis was inhibited by caspase-8 and pan caspase inhibitors but not by a caspase-9 inhibitor. Taken together, the results suggest that PPAC induces apoptosis through the death receptor-mediated apoptotic pathway where the activation of caspase-8 leads to the direct cleavage of execution caspases without the involvement of the mitochondria. Furthermore, suppressed PI3-kinase/Akt signal pathway and enhanced p53 activation after PPAC treatment suggests this to be an additional mechanism for apoptosis induction. Together, these results encourage further studies of PPAC as a promising candidate for lung cancer therapy. © 2008 Wiley-Liss, Inc. [source]

Regulation of signaling pathways involved in lupeol induced inhibition of proliferation and induction of apoptosis in human prostate cancer cells

MOLECULAR CARCINOGENESIS, Issue 12 2008
Sahdeo Prasad
Abstract Prostate cancer (PCa) is the most frequently diagnosed noncutaneous cancer and the leading cause of cancer related deaths in men in the United States and many other Asian countries. Dietary factors are considered as a strategic agent to control the risk of PCa. Lupeol, a triterpene, present in fruits and medicinal plants, has been shown to possess many pharmacological properties including anticancer effects. Here, effect of lupeol on cell proliferation and cell death was evaluated using human PCa cells, PC-3. In MTT assay, lupeol inhibited the cell proliferation (12,71%) in dose (50,800 µM) and time dependent manner. Flow-cytometric analysis of cell-cycle revealed that an antiproliferative effect of lupeol (400,600 µM) is associated with an increase in G2/M-phase arrest (34,58%). RT-PCR analysis showed that lupeol-induced G2/M-phase arrest was mediated through the inhibition of cyclin regulated signaling pathway. Lupeol inhibited the expression of cyclin B, cdc25C, and plk1 but induced the expression of 14-3-3, genes. However no changes were observed in the expression of gadd45, p21waf1/cip1 and cdc2 genes. Results of western blot showed that lupeol regulates the phosphorylation of cdc2 (Tyr15) and cdc25C (Ser198). Further, on increase of lupeol exposure to PC-3 cells an induction of apoptosis was recorded, which was associated with upregulation of bax, caspase-3, -9, and apaf1 genes and down regulation of antiapoptotic bcl-2 gene. The role of caspase-induced apoptosis was confirmed by increase in reactive oxygen species, loss of mitochondrial membrane potential followed by DNA fragmentation. Thus, our study suggests that lupeol possess novel antiproliferative and apoptotic potential against PCa. © 2008 Wiley-Liss, Inc. [source]

The mechanisms of tumor suppressor effect of glucocorticoid receptor in skin

MOLECULAR CARCINOGENESIS, Issue 8 2007
Dmitry Chebotaev
Abstract Glucocorticoid hormones exert a tumor suppressor effect in different experimental models, including mouse skin carcinogenesis. The glucocorticoid control of cellular functions is mediated via the glucocorticoid receptor (GR), a well-known transcription factor that regulates genes by DNA-binding dependent transactivation, and DNA-binding independent transrepression through negative interaction with other transcription factors. In this perspective, we analyze known mechanisms that underlie the anticancer effect of GR signaling, including effects on cell growth, differentiation, apoptosis, and angiogenesis. We also discuss a novel mechanism for the tumor suppressor effect of the GR in skin: through the regulation of the number and status of follicular epithelial stem cells (SC), which are a target cell population for skin carcinogenesis. Our studies on keratin5.GR transgenic animals that are resistant to skin carcinogenesis, demonstrated that the GR diminishes the number of follicular epithelial SCs, reduces their proliferative and survival potential and affects the expression of follicular SC "signature" genes. The analysis of global effect of the GR on gene expression in follicular epithelial SCs, basal keratinocytes, and mouse skin tumors provided an unexpected evidence that gene transrepression by GR plays an important role in the maintenance of SC and in inhibition of skin carcinogenesis by this steroid hormone receptor. It is known that antiinflammatory effect of glucocorticoids is chiefly mediated by GR transrepression. Thus, our findings suggest the similarity between the mechanisms of antiinflammatory and anticancer effects of the GR signaling. We discuss the potential clinical applications of our findings in light of drug discovery programs focused on the development of selective GR modulators that preferentially induce GR transrepression. © 2007 Wiley-Liss, Inc. [source]

Green Tea Polyphenols and Cancer Chemoprevention: Multiple Mechanisms and Endpoints for Phase II Trials

NUTRITION REVIEWS, Issue 5 2004
M.P.H., Susan B. Moyers Ph.D.
Among the numerous polyphenols isolated from green tea, the catechin EGCG predominates and is the target of anticancer research. But studies suggest that EGCG and other catechins are poorly absorbed and undergo substantial biotransformation to species that include glucuronides, sulfates, and methylated compounds. Numerous studies relate the antioxidant properties of the catechins with anticancer effects, but recent research proposes other mechanisms of action, including those involving methyl transfers that are subject to allelic variability in the enzyme catechol O-methyl transferase. However, preclinical research is promising and EGCG appears to be ready for further study in phase II and III trials. [source]

Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy

THE JOURNAL OF GENE MEDICINE, Issue 5 2009
Ryosuke Uchibori
Abstract Background Mesenchymal stem cells (MSCs) are a promising vehicle for targeted cancer gene therapy because of their potential of tumor tropism. For efficient therapeutic application, we developed retroviral vector-producing MSCs that enhance tumor transduction via progeny vector production. Methods Rat bone marrow-derived MSCs were nucleofected with the proviral plasmids (vesicular stomatitis virus-G protein-pseudotyped retroviral vector components) (VP-MSCs) or pLTR plasmid alone (non-VP-MSCs). The luciferase-based in vivo imaging system was used to assess gene expression periodically. To evaluate the anticancer effects, we administered MSCs expressing herpes simplex virus-thymidine kinase (HSV- tk) into the left ventricular cavity of nude mice engrafted with 9L glioma cells subcutaneously. Results In vivo imaging revealed that administration of luciferase-expressing non-VP-MSCs enhanced the bioluminescence signal at the inoculation sites of 9L cells, whereas no accumulation was observed in mice at the site of the control Rat-1 fibroblasts. Compared to non-VP-MSCs, the administration of VP-MSCs resulted in significant augmentation of the signal with an increase in transgene copy number. Immunohistochemical analysis showed marked luciferase expression at the tumor periphery in mice injected with VP-MSCs, whereas little expression was detected in those injected with non-VP-MSCs. Under the continuous infusion of ganciclovir, systemic administration of VP-MSCs expressing HSV- tk suppressed tumor growth more effectively than non-VP-MSC administration, whereas no anticancer effect was observed without ganciclovir treatment. Furthermore, VP-MSC administration caused no transgene transduction in the normal tissues and organs. Conclusions VP-MSCs accumulated at the site of tumors after intravascular injection in tumor-bearing mice, followed by in situ gene transfer to tumors without transduction of normal organs. When applied to the HSV- tk/ganciclovir suicide gene therapy, more efficient tumor growth suppression was observed using VP-MSCs compared to non-VP-MSCs. This VP-MSC-based system has great potential for improved cancer gene therapy. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro

CANCER, Issue 7 2005
Kae Hashimoto M.D.
Abstract BACKGROUND Lysophosphatidic acid (LPA) induced a dose-dependent increase of cancer cell invasion by promoting Rho/Rho-associated kinase signaling. Prenylation of Rho is essential for regulating cell growth, motility, and invasion. Geranylgeranylacetone (GGA), an isoprenoid compound, is used clinically as an antiulcer drug. Recent findings suggested that GGA might inhibit the small GTPase activation by suppressing prenylation. The authors hypothesized that the anticancer effects of GGA result from the inhibition of Rho activation. METHODS The authors examined the effect of GGA using an in vitro invasion assay in human ovarian carcinoma cells, and analyzed the mechanism of the GGA effect on Rho activation, stress fiber formation and focal adhesion assembly, which are essential processes for cell invasion. RESULTS The induction of ovarian carcinoma cell invasion by LPA was inhibited by the addition of GGA in a dose-dependent manner. Treatment of cancer cells with GGA resulted in inactivation of Rho, changes in cell morphology, loss of stress fiber formation and focal adhesion assembly, and the suppression of tyrosine phosphorylation of focal adhesion proteins. The effect of GGA on cancer cells was partially prevented by the addition of geranylgeraniol, which is an intermediate of geranylgeranyl pyrophosphate and compensates geranylgeranylation of Rho. CONCLUSIONS The inhibition of LPA-induced invasion by GGA was, at least in part, derived from suppressed Rho activation by preventing geranylgeranylation. Cancer 2005. © 2005 American Cancer Society. [source]

Docetaxel enhances the cytotoxicity of cisplatin to gastric cancer cells by modification of intracellular platinum metabolism

CANCER SCIENCE, Issue 8 2004
Shingo Maeda
We have examined the combined anticancer effects of docetaxel (DOC) and cisplatin (CDDP) in vitro using the gastric cancer cell lines MKN-45, MKN-74, and TMK-1. Treatment of the cell lines with 30 ,g/ml of DOC for 24 h followed by incubation with 3 or 10 ,g/ml of CDDP for 24 h showed a clear synergistic effect. Sequence dependency of the agents was observed in these cell lines: DOC followed by CDDP (DC) showed a stronger antitumor effect than CDDP followed by DOC (CD) in all cell lines. To clarify the mechanism of action of the DC combination, total intracellular platinum (Pt) levels were evaluated after treatment with CDDP alone or combined with DC. For the MKN-45 and -74 cell lines, cells treated with DOC (10 ,g/ml for 12 h) and then CDDP showed significantly increased intracellular Pt accumulation compared to cells treated with CDDP alone. We also investigated alterations in intracellular glutathione (GSH) concentration in response to DOC and CDDP. MKN-45 and -74 cells pretreated with DOC (10 ,g/ml for 12 h) showed significantly increased intracellular GSH levels compared to cells administered CDDP only. To explain these findings, messenger RNA (mRNA) levels for multidrug resistance-associated protein-1 (MRP-1), the ATP-dependent pump for Pt-GSH complexes, were quantified in CDDP-treated MKN-45 cells with and without DOC pretreatment. While CDDP administration increased MRP-1 mRNA expression in MKN-45 cells, MRP-1 was not up-regulated after CDDP administration in DOC pretreated MKN-45 cells. Our results suggested that the enhanced CDDP toxicity due to DOC pretreatment may be related to the accumulation of intracellular Pt-GSH complexes, because DOC appears to suppress the MRP-1 up-regulation induced by CDDP exposure in gastric cancer cells. [source]