Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma

Our plain-English summary of Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma, by B.A. Jacobson, E.Z. Chen, S. Tang, et al (Genes & Cancer, 2015).

The study

• Authors: B.A. Jacobson, E.Z. Chen, S. Tang, H.S. Belgum, J.A. McCauley, K.A. Evenson, R.G. Etchison, J. Jay-Dixon, M.R. Patel, A. Raza, A.K. Saluja, J. D'Cunha, R.A. Kratzke
• Journal: Genes & Cancer
• Published: 2015;6(3-4):144-52
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is a devastating disease with a poor prognosis for which there is a clear need for more successful therapeutic approaches. Triptolide, a diterpenoid triepoxide, is a highly effective agent against several cancer types in animal models. Owing to triptolide's poor solubility in water, a water-soluble analog, minnelide, was synthesized. Minnelide is a prodrug of triptolide and is activated by exposure to phosphatases that are found in all body tissues, including blood. Mesothelioma cells were treated in vitro with minnelide or its parent compound, triptolide. Minnelide and triptolide were both found to significantly reduce mesothelioma cell viability and induce apoptosis. The level of Hsp70, a protein that promotes cancer cell survival, was measured in mesothelioma cells before and after treatment with triptolide. Hsp70 levels were decreased in a dose-dependent manner. In addition, triptolide sensitized cells to gemcitabine and pemetrexed as measured by cell viability. Mice bearing mesothelioma flank tumors were treated with daily injections (28 d) of minnelide or saline solution and xenograft tumor growth recorded. Mice displayed significantly reduced tumor burden. These findings support the clinical evaluation of minnelide therapy for mesothelioma.

In plain English

This was a laboratory study using human mesothelioma cell lines and mice. It did not involve patients or asbestos exposure. The authors tested triptolide, a compound from a Chinese medicinal herb, and minnelide, a water-soluble form that is converted into triptolide. At 100 nM, both drugs reduced living cells in four mesothelioma cell lines to less than 11% of untreated cells. The cancer cell lines had on average 2.4 times more of the protein Hsp70 than normal mesothelial cells, and higher triptolide doses lowered Hsp70 in three of the four lines. Triptolide increased markers of programmed cell death and added to cell killing by the chemotherapy drugs pemetrexed and gemcitabine. In mice carrying tumors from two cell lines, with ten mice per group, 28 days of daily minnelide injections left final tumor weights at 31% and 14.8% of those in saline-treated mice. The authors concluded that this supports further clinical development of minnelide for mesothelioma. They noted that the safety of combining it with chemotherapy would need testing in phase I studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on cultured human mesothelioma cell lines plus an animal experiment in mice carrying transplanted human mesothelioma tumors (xenografts)
• Who was studied: Four human malignant mesothelioma cell lines (H513, H2373, H2461, H2596), one epithelioid and two sarcomatoid among them as named by the authors. Non-transformed human mesothelial cells (LP9) were used for comparison. Nude mice were injected in the flank with H2373 or H513 cells, with ten mice in each treatment and control cohort. The work was done at the University of Minnesota.
• Exposure: No asbestos exposure was studied. The exposures were the drugs triptolide and minnelide. In cells: 100 nM, and a range of triptolide doses, alone or combined with pemetrexed or gemcitabine. In mice: daily intraperitoneal minnelide 0.42 mg/kg starting five days after tumor implantation, for twenty-eight days, compared with saline (PBS) injections.
• Main results:
  • In the four mesothelioma cell lines, 100 nM of either triptolide or minnelide reduced cell viability to less than 11% of untreated control.
  • The concentration of triptolide that halved cell growth (IC50) was 6.28 nM for H513 cells and 4.24 nM for H2373 cells.
  • Hsp70 levels in the mesothelioma cell lines were on average 2.4 fold (range 1.55-2.81) those of normal LP9 mesothelial cells.
  • Triptolide decreased Hsp70 in a dose-dependent way in three of the four cell lines. In H2461 cells, Hsp70 rose at lower doses and fell at the highest doses.
  • After 100 nM triptolide for 48 hours, cells positive for the apoptosis marker Annexin V rose from 12.3 to 39.8% in H513 cells and from 13 to 54% in H2373 cells.
  • Adding triptolide increased pemetrexed-induced cell death by 30.8% (H513), 29.8% (H2373), 33.6% (H2461) and 27.2% (H2596), compared with pemetrexed alone.
  • Adding triptolide increased gemcitabine-induced cell death by 58.7% (H513), 27.6% (H2373), 37.7% (H2461) and 45.7% (H2596), compared with gemcitabine alone. The combination gave significantly lower viability than either drug alone in three of the four cell lines.
  • In mice, tumor volume at the end of the experiment was reduced 3.25 fold for H2373 and 7.1 fold for H513 tumors in minnelide-treated mice compared with saline-treated controls (p<0.02).
  • Final tumor weight in minnelide-treated mice was 31% (H2373) and 14.8% (H513) of tumor weight in saline-treated mice (p<0.006).
• The authors' conclusion: The authors concluded that the significant reduction of tumor burden in mesothelioma xenografts supports further clinical development of minnelide as a therapy for patients with mesothelioma.
• Limitations the authors state:
  • The authors stated that the safety of combining minnelide with chemotherapy would have to be proven in phase I studies.
  • The combination experiments with chemotherapy used triptolide, not minnelide.
  • In the H2461 cell line, the drugs killed cells without a substantial change in Hsp70. The authors suggested that Hsp70 does not play a major role in that line.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Apoptosis, Gemcitabine, Pemetrexed (Alimta), Tumor Burden.

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