Sensitivity to cis-diamminedichloroplatinum in human cancer cells is related to expression of cyclin D1 but not C-RAF-1 protein

Warenius, Hilmar M.; Seabra, Laurence; Maw, Paula

doi:10.1002/(sici)1097-0215(19960717)67:2<224::aid-ijc13>3.0.co;2-b

Cited by 41 publications

(24 citation statements)

References 19 publications

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“…Here, our IHC results has provided evidence indicating that ACA was not only able to down-regulate NF-κB activation, but also reduce the expression of NF-κB-regulated genes such as proinflammatory (NF-κB and COX-2) and proliferative (cyclin D1), which are up-regulated in most human oral neoplasia [37,38]. This was found to be a favourable observation based on past reports, where higher levels of cyclin D1 expression exhibited higher resistance to CDDP, and a reduction in its expression resulted in increased sensitivity [39]. …”

Section: Discussionmentioning

confidence: 84%

1’-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations

Arshad

Ibrahim

et al. 2012

BMC Complement Altern Med

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BackgroundOral cancers although preventable, possess a low five-year survival rate which has remained unchanged over the past three decades. In an attempt to find a more safe, affordable and effective treatment option, we describe here the use of 1’S-1’-acetoxychavicol acetate (ACA), a component of Malaysian ginger traditionally used for various medicinal purposes.MethodsWhether ACA can inhibit the growth of oral squamous cell carcinoma (SCC) cells alone or in combination with cisplatin (CDDP), was explored both in vitro using MTT assays and in vivo using Nu/Nu mice. Occurrence of apoptosis was assessed using PARP and DNA fragmentation assays, while the mode of action were elucidated through global expression profiling followed by Western blotting and IHC assays.ResultsWe found that ACA alone inhibited the growth of oral SCC cells, induced apoptosis and suppressed its migration rate, while minimally affecting HMEC normal cells. ACA further enhanced the cytotoxic effects of CDDP in a synergistic manner as suggested by combination index studies. We also found that ACA inhibited the constitutive activation of NF-κB through suppression of IKKα/β activation. Human oral tumor xenografts studies in mice revealed that ACA alone was as effective as CDDP in reducing tumor volume, and further potentiated CDDP effects when used in combination with minimal body weight loss. The effects of ACA also correlated with a down-regulation of NF-κB regulated gene (FasL and Bim), including proinflammatory (NF-κB and COX-2) and proliferative (cyclin D1) biomarkers in tumor tissue.ConclusionOverall, our results suggest that ACA inhibits the growth of oral SCC and further potentiates the effect of standard CDDP treatment by modulation of proinflammatory microenvironment. The current preclinical data could form the basis for further clinical trials to improve the current standards for oral cancer care using this active component from the Malaysian ginger.

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Section: Discussionmentioning

confidence: 84%

1’-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations

Arshad

Ibrahim

et al. 2012

BMC Complement Altern Med

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“…There are several potential molecular mechanisms that could be responsible for this drug resistance. For example, Warenius et al reported that upregulated cyclinD1 might be responsible for cis-diamminedichloroplatinum (CDDP) resistance in cancer cells [20], and Zhang et al suggested that the cell cycle inhibitor p21 waf1 might synergize with bcl-2 to confer drug resistance by inhibiting anti-cancer drug induced-apoptosis [21]. Indeed, our study shows that a reduced S phase of the cell cycle is associated with decreased cyclinD1 and increased p21 waf1 expression after TGF-β1 treatment.…”

Section: Discussionmentioning

confidence: 99%

“…This is particularly important in pancreatic cancer chemotherapy because more than 50% of pancreatic cancers have inactivated Smad4 protein [20], which may result in activation of the Smad4-independent TGF-β1 pathway when patients undergo such treatment. In this study, we determined whether TGF-β1 is associated with drug resistance in pancreatic cancer and then explored the possible underlying mechanism.…”

Section: Introductionmentioning

confidence: 99%

PKCα-induced drug resistance in pancreatic cancer cells is associated with transforming growth factor-β1

Chen

et al. 2010

J Exp Clin Cancer Res

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BackgroundDrug resistance remains a great challenge in the treatment of pancreatic cancer. The goal of this study was to determine whether TGF-β1 is associated with drug resistance in pancreatic cancer.MethodsPancreatic cancer BxPC3 cells were stably transfected with TGF-β1 cDNA. Cellular morphology and cell cycle were determined and the suppressive subtracted hybridization (SSH) assay was performed to identify differentially expressed genes induced by TGF-β1. Western blotting and immunohistochemistry were used to detect expression of TGF-β1-related genes in the cells and tissue samples. After that, the cells were further treated with an anti-cancer drug (e.g., cisplatin) after pre-incubated with the recombinant TGF-β1 plus PKCα inhibitor Gö6976. TGF-β1 type II receptor, TβRII was also knocked down using TβRII siRNA to assess the effects of these drugs in the cells. Cell viability was assessed by MTT assay.ResultsOverexpression of TGF-β1 leads to a markedly increased invasion potential but a reduced growth rate in BxPC3 cells. Recombinant TGF-β1 protein increases expression of PKCα in BxPC3 cells, a result that we confirmed by SSH. Moreover, TGF-β1 reduced the sensitivity of BxPC3 cells to cisplatin treatment, and this was mediated by upregulation of PKCα. However, blockage of PKCα with Gö6976 and TβRII with siRNA reversed the resistance of BxPC3 cells to gemcitabine, even in the presence of TGF-β1. Immunohistochemical data show that pancreatic cancers overexpress TGF-β1 and P-gp relative to normal tissues. In addition, TGF-β1 expression is associated with P-gp and membranous PKCα expression in pancreatic cancer.ConclusionsTGF-β1-induced drug resistance in pancreatic cancer cells was associated with PKCα expression. The PKCα inhibitor Gö6976 could be a promising agent to sensitize pancreatic cancer cells to chemotherapy.

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“…In these studies, cisplatin- and fluoropyrimidine-mediated apoptosis was enhanced by approximately 3-fold in Cyclin D1-overexpressing pancreatic tumor cells delivered Cyclin D1 siRNA relative to cells treated with a control siRNA [294]. Several studies have also demonstrated that the anti-apoptotic, tumorigenic activity of D-type cyclins (D1, D2, and D3) may be dependent on cooperative interaction with other growth promoting genes such as c-Myc and Ras [296, 297]. For example, co-expression of c-Myc and cyclin D3 promotes lymphoid cell resistance to dexamethasone-induced apoptosis, and overexpression of cyclin D1 inhibits drug-induced apoptosis in rat embryo fibroblasts ectopically expressing c-myc [298].…”

Section: Pro-apoptotic Rnai Therapeutic Applicationsmentioning

confidence: 99%

Delivery of Intracellular-Acting Biologics in Pro-Apoptotic Therapies

Li¹,

Nelson²,

Evans³

et al. 2011

Current Pharmaceutical Design

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The recent elucidation of molecular regulators of apoptosis and their roles in cellular oncogenesis has motivated the development of biomacromolecular anticancer therapeutics that can activate intracellular apoptotic signaling pathways. Pharmaceutical scientists have employed a variety of classes of biologics toward this goal, including antisense oligodeoxynucleotides, small interfering RNA, proteins, antibodies, and peptides. However, stability in the in vivo environment, tumor-specific biodistribution, cell internalization, and localization to the intracellular microenvironment where the targeted molecule is localized pose significant challenges that limit the ability to directly apply intracellular-acting, pro-apoptotic biologics for therapeutic use. Thus, approaches to improve the pharmaceutical properties of therapeutic biomacromolecules are of great significance and have included chemically modifying the bioactive molecule itself or formulation with auxiliary compounds. Recently, promising advances in delivery of pro-apoptotic biomacromolecular agents have been made using tools such as peptide “stapling”, cell penetrating peptides, fusogenic peptides, liposomes, nanoparticles, smart polymers, and synergistic combinations of these components. This review will discuss the molecular mediators of cellular apoptosis, the respective mechanisms by which these mediators are dysregulated in cellular oncogenesis, the history and development of both nucleic-acid and amino-acid based drugs, and techniques to achieve intracellular delivery of these biologics. Finally, recent applications where pro-apoptotic functionality has been achieved through delivery of intracellular-acting biomacromolecular drugs will be highlighted.

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Sensitivity to cis-diamminedichloroplatinum in human cancer cells is related to expression of cyclin D1 but not C-RAF-1 protein

Cited by 41 publications

References 19 publications

1’-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations

1’-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations

PKCα-induced drug resistance in pancreatic cancer cells is associated with transforming growth factor-β1

Delivery of Intracellular-Acting Biologics in Pro-Apoptotic Therapies

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