Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors

Haefner, Martin; Bluethner, Thilo; Niederhagen, Manuel; Moebius, Christian; Wittekind, Christian; Mössner, Joachim; Caca, Karel; Wiedmann, Marcus

doi:10.3748/wjg.14.3681

Cited by 28 publications

(21 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have shown that HDACis have the potential to inhibit carcinogenesis and fibrogenesis (2,(9)(10)(11)(12)(13)(14)(15). VPA, a semiselective HDACi (20), is widely prescribed for patients with epilepsy and psychiatric disorders and well tolerated by the majority of patients (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…Histone acetylation and deacetylation is controlled by histone acetyltransferases and histone deacetylases. In recent years, histone deacetylase inhibitors (HDACis) showed anti-cancer activities and are, therefore, of clinical interest (9)(10)(11)(12). There are also several reports showing an antifibrogenic effect of HDACis, but the underlying mechanism is still unclear (2,(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate cell line

et al. 2011

View full text Add to dashboard Cite

Abstract. Histone acetylation and deacetylation have been thought to be related to gene expression, and there are many reports indicating that histone deacetylase inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic mediators and produce large amounts of extracellular matrix. In particular, transforming growth factor-β1 (TGF-β1) is considered as a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them. The present study aimed to clarify whether sodium valproate (VPA) has suppressive effects on cultured human HSCs (LI90). We showed that treatment with VPA had no significantly suppressive effect on cell proliferation at a concentration of 1 mM, which corresponded approximately to the serum concentration obtained by the administration of a clinical dose. However, VPA prevented the morphological changes characteristic for activation and inhibited the expression of collagen type 1 α1 (COL1A1) and TGF-β1 in activated LI90 cells at the mRNA and protein levels. Our results support the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity at 1 mM, and HDACis are expected to be used in clinical practice for the treatment of fibrotic diseases. IntroductionHepatic stellate cells (HSCs) are considered as the main source of extracellular matrix (ECM) proteins in chronic liver diseases leading to fibrosis. In a normal liver, these cells are liver-specific pericytes that serve as major vitamin A storage sites and show little proliferative activity (1). In an injured liver, however, HSCs undergo phenotypic changes termed activation in response to profibrogenic mediators such as platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), endothelin (ET)-1, and members of the transforming growth factor-β (TGF-β) family. During this phenotypic transition, HSCs express α smooth muscle actin (αSMA) and acquire the capacity to proliferate and produce excessive quantities of ECM proteins (2,3). It is reported that TGF-β and its intracellular mediators, i.e., Smad proteins, play important roles in stimulating collagen synthesis. In particular, production of TGF-β1 is enhanced by activated HSCs, and it has been considered that the effects of TGF-β1 on HSCs involve predominantly autocrine stimulation (4,5). Therefore, inhibition of TGF-β1 signals seems to be a potential target for therapeutic intervention in patients with liver fibrosis.It is considered that histone modification, particularly histone acetylation, is a key principle of epigenetic regulation of gene expression (6-8). Histone acetylation and deacetylation is controlled by histone acetyltransferases and histone deacetylases. In recent years, histone deacetylase inhibitors (HDACis) showed anti-cancer activities and are, therefore, of clinical interest (9-12). There are also several reports showing an antifibrogenic effect of HDACis, but the underlying mechanism is still un...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate cell line

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Gemcitabine, acting as an antimetabolite, can inhibit ribonucleotide reductase and DNA synthesis, and induce apoptosis [33] . Gemcitabine today remains a first-line drug for patients with advanced pancreatic cancer [7][8][9] . However, it has a narrow therapeutic index due to rapid enzyme deamination by deoxytidine deaminase into its corresponding inactive uracil derivative, and can also induce drug resistance [34,35] .…”

Section: Discussionmentioning

confidence: 99%

“…Gemcitabine is an active nucleoside analogue against a wide variety of cancers, including nonsmall cell lung cancer and pancreatic cancer [7][8][9] . Gemcitabine, acting as an antimetabolite, can inhibit ribonucleotide reductase and DNA synthesis, and induce apoptosis [33] .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Synergetic anticancer effect of combined gemcitabine and photodynamic therapy on pancreatic cancer in vivo

Xie¹,

Jia²,

Liu³

et al. 2009

WJG

View full text Add to dashboard Cite

AIM:To investigate the anti-tumor effects of combined cytotoxic drug (gemcitabine) and photodynamic therapy (PDT) on human pancreatic cancer xenograft in nude mice. METHODS:Human pancreatic cancer cell line SW1990 was used in the investigation of the in vivo effect of combined gemcitabine and PDT on human pancreatic cancer xenograft in mice. Sixty mice were randomly allocated into a control group (without treatment), photosensitizer treatment group (2 mg/kg photosan, without illumination), chemotherapy group (50 mg/kg gemcitabine i.p.), PDT group (2 mg/kg photosan + laser irradiation) and combined treatment group (photosan + chemotherapy), with 12 mice in each group. Tumor size was measured twice every week. Anti-tumor activity in different groups was evaluated by tumor growth inhibition (TGI). RESULTS:No significant anti-tumor effect was observed either in photosensitizer treatment group or in chemotherapy group. PDT led to necrosis in cancer lesions and significantly reduced tumor volume compared with photosensitizer on day 6 and at the following time points after initialization of therapy (0.24 ± 0.15-0.49 ± 0.08 vs 0.43 ± 0.18-1.25 ± 0.09, P < 0.05). PDT significantly reduced tumor volume in combined treatment group compared with photosensitizer treatment group (0.12 ± 0.07-0.28 ± 0.12 vs 0.39 ± 0.15-1.20 ± 0.11, P < 0.05), small dose chemotherapy group (0.12 ± 0.07-0.28 ± 0.12 vs 0.32 ± 0.14-1.16 ± 0.08, P < 0.05) and control group (0.12 ± 0.07-0.28 ± 0.12 vs 0.43 ± 0.18-1.25 ± 0.09, P < 0.05). TGI was higher in the combined treatment group (82.42%) than in the PDT group (58.18%). CONCLUSION:PDT has a significant anti-tumor effect, which is maintained for a short time and can be significantly enhanced by small doses of gemcitabine.

show abstract

Cytotoxic activity of the histone deacetylase inhibitor panobinostat (LBH589) in anaplastic thyroid cancer in vitro and in vivo

Catalano

Pugliese

Gargantini

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

Anaplastic thyroid carcinoma (ATC) has a rapidly fatal clinical course, being resistant to multimodal treatments. Microtubules, a/b tubulin heterodimers, are crucial in cell signaling, division and mitosis and are among the most successful targets for anticancer therapy. Panobinostat (LBH589) is a potent deacetylase inhibitor acting both on histones and nonhistonic proteins, including a-tubulin. In vitro LBH589, evaluated in three ATC cell lines (BHT-101, CAL-62 and 8305C), resulted in impairment of cell viability, inhibition of colony formation, cell cycle arrest and apoptosis induction. Mechanistically, we showed that LBH589 not only affected the expression of p21 and cyclin D1, but markedly determined microtubule stabilization as evidenced by tubulin acetylation and increased tubulin polymerization. In a SCID xenograft model implanted with CAL-62 cells, the cytotoxic properties of LBH589 were confirmed. The drug at the dose of 20 mg/kg significantly impaired tumor growth (final tumor volume 2.5-fold smaller than in untreated animals); at this dose, no relevant side effects were observed. In tumors of treated animals, a significant reduction of Ki67, which was negatively correlated with tubulin acetylation, was observed. Moreover, acetyl-tubulin levels negatively correlated with tumor volume at sacrifice, reinforcing the opinion that tubulin acetylation has a role in the inhibition of tumor growth. In conclusion, LBH589, acting on both histones and nonhistonic proteins in anaplastic thyroid cancer, appears to be a promising therapeutic agent for the treatment of this kind of cancer which is known not to respond to conventional therapy.Anaplastic thyroid carcinoma (ATC), which accounts for 1% of thyroid tumors, is one of the most lethal malignancies, with a rapidly fatal clinical course.

show abstract

Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors

Cited by 28 publications

References 50 publications

Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate cell line

Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate cell line

Synergetic anticancer effect of combined gemcitabine and photodynamic therapy on pancreatic cancer in vivo

Cytotoxic activity of the histone deacetylase inhibitor panobinostat (LBH589) in anaplastic thyroid cancer in vitro and in vivo

Contact Info

Product

Resources

About