[Rich66]

1: J Control Release. 2008 Jul 2;129(1):18-25. Epub 2008 Apr 4. Links

A potential target associated with both cancer and cancer stem cells: a combination therapy for eradication of breast cancer using vinorelbine stealthy liposomes plus parthenolide stealthy liposomes.

Liu Y, Lu WL, Guo J, Du J, Li T, Wu JW, Wang GL, Wang JC, Zhang X, Zhang Q.
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
The cancer stem cells play a critical role in both initiation and relapse of the cancers as they are resistant to the most of cytotoxic agents and able to proliferate indefinitely. Vinorelbine stealthy liposomes and parthenolide stealthy liposomes were developed for providing beneficial pharmacological properties and to eradicate cancer stem cells and non-stem cancer cells together by a combination therapy. Cytotoxicity and cancer stem-like cells (side population, SP) identification were performed on human breast cancer cell lines MCF-7 and MDA-MB-231. SP cells were further sorted from MCF-7 cells and characterized. Inhibitory effect was evaluated on the sorted SP and non-SP cells. Antitumor activity was evaluated on MCF-7 xenografts in nude mice. SP cells were identified with a higher percentage in MCF-7 cells (3.8%) and lower in MDA-MB-231 cells (0.6%). Both vinorelbine and parthenolide inhibited the proliferation in MCF-7 and MDA-MB-231 cells. As compared to non-SP cells, inhibitory effect of vinorelbine in the SP cells was lower while a robust inhibitory effect was observed when applying vinorelbine in combination with parthenolide. In the MCF-7 xenografts, stealthy liposomal vinorelbine plus stealthy liposomal parthenolide produced a full inhibitory effect. This combination therapy may provide a potential strategy for eradication of breast cancer by targeting cancer together with cancer stem cells.
PMID: 18466993 [PubMed - indexed for MEDLINE]

1: Breast Cancer Res Treat. 2008 Oct;111(3):419-27. Epub 2007 Oct 27. Links

NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells.

Zhou J, Zhang H, Gu P, Bai J, Margolick JB, Zhang Y.
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Accumulating evidence indicates that breast cancer is caused by cancer stem cells and cure of breast cancer requires eradication of breast cancer stem cells. Previous studies with leukemia stem cells have shown that NF-kappaB pathway is important for leukemia stem cell survival. In this study, by using MCF7 sphere cells as model of breast cancer stem-like cells, we evaluated the effect of NF-kappaB pathway specific inhibitors on human breast cancer MCF7 sphere cells.cells known to enrich in breast cancer stem-like cells. The preferential inhibition effec Three inhibitors including parthenolide (PTL), pyrrolidinedithiocarbamate (PDTC) and its analog diethyldithiocarbamate (DETC) were found to preferentially inhibit MCF7 sphere cell proliferation. These compounds also showed preferential inhibition in term of proliferation and colony formation on MCF7 side population (SP) cells, a small fraction of MCF7 t of these compounds was due to inhibition of the NF-kappaB activity in both MCF7 sphere and MCF7 cells, with higher inhibition effect on MCF7 sphere cells than on MCF7 cells. PDTC was further evaluated in vivo and showed significant tumor growth inhibition alone but had better tumor growth inhibition in combination with paclitaxel in the mouse xenograft model than either PDTC or paclitaxel alone. This study suggests that breast cancer stem-like cells could be selectively inhibited by targeting signaling pathways important for breast cancer stem-like cells.
PMID: 17965935 [PubMed - indexed for MEDLINE

Oncogene (2004) 23, 7330–7344. doi:10.1038/sj.onc.1207995 Published online 2 August 2004
Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase

Harikrishna Nakshatri^1,2,3,4, Susan E Rice⁵ and Poornima Bhat-Nakshatri^3,4

1. ¹Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2. ²Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3. ³Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
4. ⁴Walther Cancer Institute, Indianapolis, IN 46208, USA
5. ⁵Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Correspondence: H Nakshatri, R4-202, Indiana Cancer Research Institute, 1044 West Walnut St., Indianapolis, IN 46202, USA. E-mail: hnakshat@iupui.edu
Received 4 May 2004; Revised 25 June 2004; Accepted 27 June 2004; Published online 2 August 2004.

Top of pageAbstract

The antitumor activity of the sesquiterpene lactone parthenolide, an active ingredient of medicinal plants, is believed to be due to the inhibition of DNA binding of transcription factors NF-B and STAT-3, reduction in MAP kinase activity and the generation of reactive oxygen. In this report, we show that parthenolide activates c-Jun N-terminal kinase (JNK), which is independent of inhibition of NF-B DNA binding and generation of reactive oxygen species. Parthenolide reversed resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Cancer cells treated with a combination of TRAIL and parthenolide underwent massive typical apoptosis and atypical apoptosis involving the loss of plasma membrane integrity. JNK activity is necessary for the parthenolide-induced sensitization to TRAIL because a dominant-negative JNK or the JNK inhibitor SP600125 reduced TRAIL plus parthenolide-induced apoptosis. Parthenolide induced phosphorylation of Bid and increased TRAIL-dependent cleavage of Bid without affecting caspase 8 activities. Cytochrome c but not Smac/DIABLO was released from the mitochondria in cells treated with parthenolide alone. Parthenolide through JNK increased the TRAIL-mediated degradation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP). Enhanced XIAP cleavage correlated with increased and prolonged caspase 3 activity and PARP cleavage, suggesting that the sensitization to TRAIL involves 'feed forward' activation of caspase 3. These results identify a new antitumor activity of parthenolide, which can be exploited to reverse resistance of cancer cells to TRAIL, particularly those with elevated XIAP levels.
Keywords:

parthenolide, TRAIL, apoptosis, JNK, NF-B, breast cancer

Abbreviations:

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; JNK, c-Jun N-terminal kinase; PARP, poly(ADP-ribose) polymerase; Z-VAD-FMK, N-tert-butoxy-carbonyl-Val-Ala-Asp-fluromethyl-ketone; NF-B, nuclear factor kappaB; EMSA, electrophoretic mobility shift assay; XIAP, X-linked inhibitor of apoptosis protein; Smac, second mitochondria-derived activator of caspases; MTS, (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

Microtubule-interfering activity of parthenolide.
Chem Biol Interact. 2004 Oct 15;149(2-3):165-73.
Parthenolide is an active sesquiterpene lactone present in a variety of medicinal herbs (feverfew), well known as anti-inflammatory drug. It has recently been proposed as a chemotherapeutic drug, but the pharmacological pathways of its action have not yet been fully elucidated. Firstly, we explored whether the anticancer properties of parthenolide may be related to a tubulin/microtubule-interfering activity. We additionally compared bioactivities of parthenolide with those checked after combined treatments with paclitaxel in human breast cancer MCF-7 cells. Parthenolide exerted in vitro stimulatory activity on tubulin assembly, by inducing the formation of well-organized microtubule polymers. Light microscopy detections showed that parthenolide-induced alterations of either microtubule network and nuclear morphology happened only after combined exposures to paclitaxel. In addition, the growth of MCF-7 cells was significantly inhibited by parthenolide, which enhanced paclitaxel effectiveness. In conclusion, the antimicrotubular and antiproliferative effects of parthenolide, well known microtubule-stabilizing anticancer agent, may influence paclitaxel activity. The tubulin/microtubule system may represent a novel molecular target for parthenolide, to be utilized in developing new combinational anticancer strategies.

1: Prostate. 2009 Jun 1;69(8):827-37. Links

Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: An integrated molecular profiling approach.

Kawasaki BT, Hurt EM, Kalathur M, Duhagon MA, Milner JA, Kim YS, Farrar WL.
Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute at Frederick (NCI-Frederick), National Institutes of Health,1050Boyles Street, Frederick, MD 21702, USA.
Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1. (XBP1), and p53 In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment. (c) 2009 Wiley-Liss, Inc.
PMID: 19204913 [PubMed - indexed for MEDLINE