Suppression of 5-lipoxygenase gene is involved in triptolide-induced apoptosis in pancreatic tumor cell lines

Zhou, Guoqing; Ding, Xiaoling; Huang, Jing; Zhang, H.; Wu, Shenbao

doi:10.1016/j.bbagen.2007.03.002

Cited by 40 publications

(27 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A ). ALOX5 has previously been linked to leukemia stem cells and cancer-related signaling pathways [17], [18], [19], [20], [21]. The differential expression of ALOX5 indicates a potential role in determining sensitivity to DZNep in MM.…”

Section: Resultsmentioning

confidence: 97%

Determinants of Sensitivity to DZNep Induced Apoptosis in Multiple Myeloma Cells

Xie

Cheong

et al. 2011

PLoS ONE

View full text Add to dashboard Cite

The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM.

show abstract

Section: Resultsmentioning

confidence: 97%

Determinants of Sensitivity to DZNep Induced Apoptosis in Multiple Myeloma Cells

Xie

Cheong

et al. 2011

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…3B). Previous findings indicate that inhibition of LTB 4 production can suppress pancreatic cancer growth (30). Our data indicated that knockdown of LTA 4 H reduced anchorage-independent cell growth (Fig.…”

Section: Resultsmentioning

confidence: 98%

Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A4 Hydrolase

Jeong

Nadas

et al. 2010

Cancer Research

View full text Add to dashboard Cite

The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A4 hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol.

show abstract

“…Triptolide administered in vivo decreased pancreatic cancer growth and significantly decreased localregional tumor spread [43]. In addition, triptolide inhibition of the 5-lipoxygenase (5-LOX) pathway of arachidonic acid metabolism is associated with the anti-proliferation activity [44] and induces caspase-independent autophagic death in pancreatic metastatic cell lines S2-013, S2-VP10, and Hs766T [45]. The expression of metalloproteinase 10 (ADAM10) is increased in several tumors including leukemia and is involved in malignant cell growth and cancer progression.…”

Section: Triptolide and Autoimmune Diseasesmentioning

confidence: 99%

Triptolide and its expanding multiple pharmacological functions

Liu

2011

International Immunopharmacology

303

197

View full text Add to dashboard Cite

Suppression of 5-lipoxygenase gene is involved in triptolide-induced apoptosis in pancreatic tumor cell lines

Cited by 40 publications

References 22 publications

Determinants of Sensitivity to DZNep Induced Apoptosis in Multiple Myeloma Cells

Determinants of Sensitivity to DZNep Induced Apoptosis in Multiple Myeloma Cells

Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A4 Hydrolase

Triptolide and its expanding multiple pharmacological functions

Contact Info

Product

Resources

About