Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-κB inhibitor, DMAPT (LC-1)

Neelakantan, Sundar; Nasim, Shama; Guzmán, Mónica L.; Jordan, Craig T.; Crooks, Peter A.

doi:10.1016/j.bmcl.2009.05.092

Cited by 179 publications

(198 citation statements)

References 29 publications

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“…This finding is in keeping with the results described in chronic lymphocytic leukemia (CLL) in which parthenolide induces apoptosis in CLL cells but not in normal T-lymphocytes or bone marrow hematopoietic progenitors (13,14). LC-1 is a dimethylamino derivative of parthenolide which has >1,000-fold higher solubility than the parental molecule and hence has potential therapeutic activity (15). Studies in acute myeloid leukemia (AML) showed that AML progenitor cells were targeted by LC-1 but normal hematopoietic progenitor cells were spared (16).…”

Section: Introductionsupporting

confidence: 75%

The NF-κB Inhibitor LC-1 Has Single Agent Activity in Multiple Myeloma Cells and Synergizes with Bortezomib

Walsby

Pratt

Hewamana

et al. 2010

Molecular Cancer Therapeutics

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Multiple myeloma remains incurable with conventional therapeutics. Thus, new treatments for this condition are clearly required. In this study we evaluated the novel NF-κB inhibitor LC-1 in multiple myeloma cell lines and plasma cells derived from multiple myeloma patients. LC-1 was cytotoxic to multiple myeloma cell lines H929, U266, and JJN3, and induced apoptosis in a dose-dependent manner with an overall LD 50 of 3.6 μmol/L (±1.8) after 48 hours in culture. Primary multiple myeloma cells, identified by CD38 and CD138 positivity, had a mean LD 50 for LC-1 of 4.9 μmol/L (±1.6); normal bone marrow cells were significantly less sensitive to the cytotoxic effects of LC-1 (P = 0.0002). Treatment of multiple myeloma cell lines with LC-1 resulted in decreased nuclear localization of the NF-κB subunit Rel A and the inhibition of NF-κB target genes. In addition, LC-1 showed synergy with melphalan, bortezomib, and doxorubicin (combination indices of 0.72, 0.61, and 0.78, respectively), and was more effective when cells were cultured on fibronectin. These data show that LC-1 has activity in multiple myeloma cell lines and primary multiple myeloma cells, and its ability to inhibit NF-κB seems important for its cytotoxic effects. Furthermore, LC-1-induced transcriptional suppression of survivin and MCL1 provides a potential explanation for its synergy with conventional agents.

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Section: Introductionsupporting

confidence: 75%

The NF-κB Inhibitor LC-1 Has Single Agent Activity in Multiple Myeloma Cells and Synergizes with Bortezomib

Walsby

Pratt

Hewamana

et al. 2010

Molecular Cancer Therapeutics

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“…Despite widely documented anti-cancer activity and the absence of major adverse effects, clinical development of parthenolide is hampered by its poor water solubility, (35) thus limiting its potential as a promising clinical agent. Previous studies investigated the in vitro and in vivo activities of the water-soluble parthenolide analogue dimethylaminoparthenolide (DMAPT) (20,35,36) and reported that this analogue suppressed tumor growth by targeting NF-κB and generating reactive oxygen (37)(38)(39). The water-soluble parthenolide analogue may become a more readily available radio-sensitizing agent, but further investigation is needed to elucidate its efficacy and spectrum as a radio-sensitizing agent.…”

Section: Discussionmentioning

confidence: 99%

Radio-sensitization of the murine osteosarcoma cell line LM8 with parthenolide, a natural inhibitor of NF-κB

et al. 2011

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Abstract. Nuclear factor (NF)-κB has been shown to be associated with cancer resistance to radiotherapy (RT), and is constitutively active in the murine osteosarcoma cell line, LM8. Parthenolide has been reported to show antitumor activity through inhibition of the NF-κB pathway. In this study, we investigated the radio-sensitizing activity of parthenolide. We established Luc-LM8, a stable transfectant reporter construct of NF-κB transcriptional activity into LM8. Luc-LM8 maintained the malignancy observed with LM8. In vitro, Luc-LM8 cells were cultured with or without parthenolide treatment, irradiated, and subjected to cell viability and apoptosis assays. In vivo, to investigate whether parthenolide enhances radio-sensitivity of tumors, a tumor growth assay was conducted. Parthenolide enhanced the growth inhibitory effect of RT and induced the apoptosis of Luc-LM8 cells with RT in vitro. The in vivo tumor growth was significantly suppressed in the mice treated with parthenolide and RT. The present study suggests that parthenolide sensitizes Luc-LM8 cells to irradiation. Thus, parthenolide is a potential candidate for use as a potent radio-sensitizing drug for use in cancer RT.

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“…This increased sensitivity to parthenolide may be due to differences in the experimental protocols or may be due to parthenolide administration orally (46) versus intraperitoneally in our studies. In fact, parthenolide is not orally bioavailable (47), resulting in the recent synthesis of an orally bioavailable derivative, dimethylamino-parthenolide (48), which is currently being tested in cancer clinical trials (10). Furthermore, in the xenograft models used in this study, parthenolide may be reducing tumor volumes by modifying host cells and subsequent interactions with tumor cells.…”

Section: Tumor Cell Injection Ptlmentioning

confidence: 99%

Inhibition of Tumor Promotion by Parthenolide: Epigenetic Modulation of p21

Ghantous

Saikali

Rau

et al. 2012

Cancer Prevention Research

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The promotion stage in the multistep process of epidermal tumorigenesis is NF-kB-dependent, epigenetically regulated, and reversible, thus, a suitable target for chemoprevention. We investigated whether the NF-kB inhibitor, parthenolide, currently in cancer clinical trials, attenuates tumor promotion by modulating the epigenetically regulated NF-kB target genes, p21 and cyclin D1.Parthenolide selectively inhibited the growth of neoplastic keratinocytes while sparing normal ones. Specifically, in JB6Pþ cells, a model of tumor promotion, noncytotoxic parthenolide concentrations abrogated tumor promoter-induced cell proliferation and anchorage-independent growth. Furthermore, parthenolide decreased tumor promoter-induced NF-kB activity, increased p21, and decreased cyclin D1 expression. In parthenolide-treated cells, p21 transcription correlated with relaxed chromatin and p65/NFkB binding at the p21 promoter. However, cyclin D1 transcription correlated more with p65/NF-kB binding than with chromatin structure at the cyclin D1 promoter. Epigenetic regulation by parthenolide seemed specific, as parthenolide did not alter global histone acetylation and methylation and histone deacetylase activity. Because p21 expression by parthenolide was sustained, we used p21-siRNA and p21À/À cancer cells and showed that the loss of p21 is cytoprotective against parthenolide.Low parthenolide concentrations (0.25 mg/kg) inhibited tumor growth of promoted JB6Pþ cells in xenograft immunocompromised mice using two different chemoprevention protocols. Tissue microarray of mouse tumors showed that parthenolide decreased scores of the cell proliferation marker Ki67 and p65/NFkB, whereas it increased p21 expression.These results show that low doses of parthenolide inhibit tumor promotion and epigenetically modulate p21 expression, highlighting the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy. Cancer Prev Res; 5(11); 1298-309. Ó2012 AACR.

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Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-κB inhibitor, DMAPT (LC-1)

Cited by 179 publications

References 29 publications

The NF-κB Inhibitor LC-1 Has Single Agent Activity in Multiple Myeloma Cells and Synergizes with Bortezomib

The NF-κB Inhibitor LC-1 Has Single Agent Activity in Multiple Myeloma Cells and Synergizes with Bortezomib

Radio-sensitization of the murine osteosarcoma cell line LM8 with parthenolide, a natural inhibitor of NF-κB

Inhibition of Tumor Promotion by Parthenolide: Epigenetic Modulation of p21

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