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Combined treatment of pancreatic cancer with mithramycin A and tolfenamic acid promotes Sp1 degradation and synergistic antitumor activity.

ABSTRACT: Mithramycin (MIT) and tolfenamic acid (TA) inhibit the activity of the transcription factor Sp1. In the present study, we investigated whether pancreatic cancer treatment with a combination of these compounds has a synergistic effect on Sp1 activity, tumor growth, and their underlying response mechanisms. Treatment of pancreatic tumor xenografts with MIT and TA produced dose-dependent antitumor activity, and significant antitumor activity of either compound alone was directly associated with systemic side effects. Combination treatment with nontoxic doses of both compounds produced synergistic antitumor activity, whereas treatment with a nontoxic dose of either compound alone lacked a discernible antitumor effect. Synergistic therapeutic effects correlated directly with synergistic antiproliferation and antiangiogenesis in vitro. Moreover, combination treatment resulted in Sp1 protein degradation, drastically downregulating expression of Sp1 and vascular endothelial growth factor. Our findings established that Sp1 is a critical target of TA and MIT in human pancreatic cancer therapy, rationalizing clinical studies to determine the effect of existing pancreatic cancer therapy regimens on Sp1 signaling in tumors and normal pancreatic tissue, and the ability of Sp1-targeting strategies to modify cancer responses.

SUBMITTER: Jia Z

PROVIDER: S-EPMC2840649 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Combined treatment of pancreatic cancer with mithramycin A and tolfenamic acid promotes Sp1 degradation and synergistic antitumor activity.

Jia Zhiliang Z Gao Yong Y Wang Liwei L Li Qiang Q Zhang Jun J Le Xiangdong X Wei Daoyan D Yao James C JC Chang David Z DZ Huang Suyun S Xie Keping K

Cancer research 20100119 3

Mithramycin (MIT) and tolfenamic acid (TA) inhibit the activity of the transcription factor Sp1. In the present study, we investigated whether pancreatic cancer treatment with a combination of these compounds has a synergistic effect on Sp1 activity, tumor growth, and their underlying response mechanisms. Treatment of pancreatic tumor xenografts with MIT and TA produced dose-dependent antitumor activity, and significant antitumor activity of either compound alone was directly associated with sys ...[more]

PMID: 20086170

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Project description:Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for >48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1-2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P<0.01). Moreover, the treatment of MIT and MIT-NPs reduced the expression level of oncogene c-Myc regulated by Sp1, and notably, both of them decreased the protein level of CD47. In summary, the novel formulation of MIT-NPs shows highly therapeutic efficacy against pancreatic carcinoma xenograft. In addition, MIT-NPs can downregulate CD47 expression, implying that it might play a positive role in cancer immunotherapy.

Project description:Background5-Florouracil (5-FU) is a commonly used chemotherapeutic drug for cholangiocarcinoma, whereas it has unsatisfactory effect, and patients often have chemo-resistance to it. The combination of chemotherapeutic agents and traditional Chinese medicine has already exhibited a promising application in oncotherapy. Huaier extract (Huaier) has been used in clinical practice widely, exhibiting good anti-tumor effect. This paper aims to investigate the possibility of combination 5-FU and Huaier as a treatment for cholangiocarcinoma.MethodsA series of experiments were performed on the Huh28 cells in vitro, which involved cell proliferation, colony formation, apoptosis, cell cycle, migratory and invasive tests. Besides, western blots were also performed to examine the potential mechanism of 5-FU.ResultsThe combination effect (antagonism, synergy or additive) was assessed using Chou-Talalay method. Using the CCK-8 and Colony formation assay, the anti-proliferation effect of 5-FU combined with Huaier was observed. Apoptosis inducing and cell cycle arrest effect of the combination of two drugs were assessed by flow cytometry. To determine the combined treatment on cell immigration and invasion ability, wound healing and Transwell assay were performed. The above experiment results suggest that the combined 5-FU and Huaier, compared with treatment using either drug alone, exhibited stronger effects in anti-proliferation, cycle arrest, apoptosis-induced and anti-metastasis. Further, western blot results reveal that the inhibition of STAT3 and its target genes (e.g. Ki67, Cyclin D1, Bcl-2 and MMP-2) might be set as the potential therapeutic targets. Besides, the inhibition of combination treatment in proteins expression associated with proliferation, apoptosis, cell cycle and metastasis was consistent with that of previous phenotypic experiments.ConclusionsHuaier combined with 5-FU exhibited a synergistic anti-tumor effect in Huh28 cell. Furthermore, the mechanisms might be associated with the activation and translocation of STAT3, as well as its downstream genes.

Project description:Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of tumor growth. While single agent cediranib or SC68896 treatment did not alter tumor growth or survival, combined cediranib/SC68896 significantly delayed tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased tumor necrosis in the cediranib/SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined cediranib/SC68896 group versus untreated. Consistent with our previous findings, cediranib alone did not significantly alter mean tumor rCBF, rCBV, rMTT, or Ktrans. In contrast, SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined cediranib/SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined cediranib/SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the combination of cediranib with a proteasome inhibitor substantially increases the anti-angiogenic efficacy produced from either agent alone, and synergistically slows glioma tumor growth and extends survival, suggesting a promising treatment which warrants further investigation.

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Combined treatment of pancreatic cancer with mithramycin A and tolfenamic acid promotes Sp1 degradation and synergistic antitumor activity.

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Combined treatment of pancreatic cancer with mithramycin A and tolfenamic acid promotes Sp1 degradation and synergistic antitumor activity.

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