Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo

Roušalová, Ilona; Banerjee, Sulagna; Sangwan, Veena; Evenson, Kristen; McCauley, Joel; Kratzke, Robert A.; Vickers, Selwyn M.; Saluja, Ashok K.; D’Cunha, Jonathan

doi:10.1371/journal.pone.0077411

Cited by 45 publications

(54 citation statements)

References 87 publications

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“…Previous studies have shown that Minnelide, a water soluble analog of triptolide, is effective in pancreatic, gastric and osteosarcoma [9,10,3, 5,13]. We have found that Minnelide is an active agent against ovarian cancer both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 76%

“…Others have shown that Minnelide exhibits anti-proliferative effects in non-small cell lung cancer by promoting apoptosis in vitro and in vivo [10]. Further, Minnelide has been shown to reduce tumor burden and metastasis in an orthotopic model of osteosarcoma [9].…”

Section: Discussionmentioning

confidence: 99%

“…The conversion of triptolide to Minnelide has been shown previously both in vitro and in vivo [6]. This compound has been found to be effective against pancreatic cancer as well as osteosarcoma and non-small cell lung cancer both in vitro and in vivo [6,9,10]. Since both pancreatic and ovarian cancers metastasize in the peritoneum, we sought to determine the efficacy of Minnelide in inhibiting ovarian cancer growth.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug

Rivard

Geller

Schnettler

et al. 2014

Gynecologic Oncology

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Objective Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo. Methods The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth. Results Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice. Conclusions Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug

Rivard

Geller

Schnettler

et al. 2014

Gynecologic Oncology

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“…Triptolide induces cell death in pancreatic cancer cells and markedly reduces the growth and loco-regional spread of pancreatic tumors in animal models (4). We have also shown that triptolide is effective against osteosarcoma (5), lung cancer (6), cholangiocarcinoma (7) and neuroblastoma (8). Others have shown that triptolide is effective against melanoma (9), gastric (9), breast (9) and colon cancer (10, 11).…”

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confidence: 94%

Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F

Oliveira

Beyer

Chugh

et al. 2015

Laboratory Investigation

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Background Despite significant progress in diagnostics and therapeutics, over fifty thousand patients die from colorectal cancer annually. Hence there is urgent need for new lines of treatment. Triptolide, a natural compound isolated from the Chinese herb Tripterygium wilfordii, is effective against multiple cancers. We have synthesized a water soluble analog of triptolide, named Minnelide, which is currently in phase I trial against pancreatic cancer. The aims of the current study were to evaluate whether triptolide/Minnelide is effective against colorectal cancer and to elucidate the mechanism by which triptolide induces cell death in colorectal cancer. Methods Efficacy of Minnelide was evaluated in subcutaneous xenograft and liver metastasis model of colorectal cancer. For mechanistic studies colon cancer cell lines HCT116 and HT29 were treated with triptolide and the effect on viability, caspase activation, annexin positivity, lactate dehydrogenase(LDH) release and cell cycle progression was evaluated. Effect of triptolide on E2F transcriptional activity, mRNA levels of E2F dependent genes, E2F1-Rb binding and proteins levels of regulator of G1-S transition was also measured. DNA binding of E2F1 was evaluated by chromatin immunoprecipitation assay. Results Triptolide decreased colon cancer cell viability in a dose- and time-dependent fashion. Minnelide markedly inhibited the growth of colon cancer in the xenograft and liver metastasis model of colon cancer and more than doubles the median survival of animals with liver metastases from colon cancer. Mechanistically we demonstrate that at low concentrations, triptolide induces apoptotic cell death but at higher concentrations it induces cell cycle arrest. Our data suggest that triptolide is able to induce G1 cell cycle arrest by inhibiting transcriptional activation of E2F1. Our data also show that triptolide downregulates E2F activity by potentially modulating events downstream of DNA binding. Conclusion Triptolide and Minnelide are effective against colon cancer in multiple pre-clinical models.

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“…Inhibition of this pathway may prove clinically effective in decreasing metastatic spread. Minnelide™, a pro-drug derived from triptolide, has been shown in several cancers to downregulate NF-κB activity 17-19 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NF-kappa B pathway leads to deregulation of epithelial–mesenchymal transition and neural invasion in pancreatic cancer

Nomura

Majumder

Giri

et al. 2016

Laboratory Investigation

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NF-κB plays an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreased overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits NGF mediated and neural-tumor co-culture in vitro invasion and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

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Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo

Cited by 45 publications

References 87 publications

Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug

Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug

Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F

Inhibition of NF-kappa B pathway leads to deregulation of epithelial–mesenchymal transition and neural invasion in pancreatic cancer

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