Picropodophyllin inhibits the growth of pemetrexed-resistant malignant pleural mesothelioma via microtubule inhibition and IGF-1R-, caspase-independent pathways

Our plain-English summary of Picropodophyllin inhibits the growth of pemetrexed-resistant malignant pleural mesothelioma via microtubule inhibition and IGF-1R-, caspase-independent pathways, by R. Sun, R. Tanino, X. Tong, et al (Translational Lung Cancer Research, 2022).

The study

• Authors: R. Sun, R. Tanino, X. Tong, E.F. Haque, Y. Amano, T. Isobe, Y. Tsubata
• Journal: Translational Lung Cancer Research
• Published: 2022;11(4):543-559
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Acquired pemetrexed resistance leads to treatment interruption in patients with malignant pleural mesothelioma (MPM). Insulin-like growth factor-I receptor (IGF-1R) inhibitor is a candidate for treating pemetrexed-naïve MPM. However, the efficacy of cytotoxic and targeted drugs in acquired-pemetrexed resistant MPM is unclear. We explored anticancer drugs, including the IGF-1R inhibitor picropodophyllin, against acquired pemetrexed-resistant MPMs.

Methods: Acquired pemetrexed-resistant human MPM cell lines, named as H2452/PEM and 211H/PEM after their parental lines H2452 and 211H, respectively, were established by exposure to pemetrexed in vitro. Picropodophyllin and siRNA for IGF-1R knockdown were used to evaluate the efficacy of IGF-1R inhibition. Immunofluorescence was used to evaluate microtubule localization. The efficacy of picropodophyllin was evaluated in 3-dimensional MPM models.

Results: The acquired pemetrexed-resistant MPM lines retained their resistance after the removal of culture treatment. IGF-1R levels in H2452/PEM cells were higher than those in H2452 cells but not in 211H/PEM cells compared to the respective parental line. Picropodophyllin induced sub-G1 arrest in H2452/PEM cells but induced G2/M phase arrest in 211H/PEM cells, leading to caspase-independent cell death in the two acquired pemetrexed-resistant MPM lines. Although picropodophyllin inhibited phosphorylation of IGF-1R, specific inhibition of IGF-1R by RNA interference did not reduce the viability of pemetrexed-resistant MPM lines. Additionally, picropodophyllin reduced the viability of both IGF-1R knockdown pemetrexed-resistant MPM cells. Picropodophyllin was cytotoxic in acquired-pemetrexed-resistant MPM lines because of inhibition of microtubule formation and induction of aberrant mitosis. Moreover, combination treatment with picropodophyllin and vinorelbine synergistically affected the pemetrexed-resistant MPM lines but not the parental lines. Furthermore, we observed a similar efficacy of picropodophyllin in 3-dimensional pemetrexed-resistant MPM models.

Conclusions: Picropodophyllin may offer novel therapeutic properties for treating acquired pemetrexed-resistant MPM. Targeting tubulin may be an important strategy in the treatment of MPM after the discontinuation of pemetrexed.

2022 Translational Lung Cancer Research. All rights reserved.

In plain English

This was a laboratory study of cancer cells grown in dishes. It involved no patients, animals, or study of asbestos exposure. The authors used two human malignant pleural mesothelioma (MPM) cell lines, H2452 (epithelial type) and MSTO-211H (biphasic type). They grew these for about 50 passages in rising concentrations of the chemotherapy drug pemetrexed, producing resistant versions called H2452/PEM and 211H/PEM. They then tested picropodophyllin, a drug described as an IGF-1R inhibitor. Picropodophyllin reduced the viability of both resistant lines more than that of the original lines, causing caspase-independent cell death. Reducing IGF-1R levels with siRNA, a gene knockdown method, did not lower the resistant cells' viability. The authors reported that picropodophyllin acted by inhibiting microtubule formation and not by IGF-1R inhibition alone. Combined with vinorelbine, picropodophyllin had a synergistic effect in the resistant lines only. Resistant lines were also more sensitive in three-dimensional cell models. The authors concluded that picropodophyllin may be more effective against pemetrexed-resistant MPM than pemetrexed-naïve MPM. They noted that only two pairs of cell lines were used and no in vivo experiments were done.

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 (in vitro) cell-line study, including monolayer cultures, 3-dimensional spheroids and 3-dimensional tumor models; no patients or animals
• Who was studied: Two human MPM cell lines obtained from the American Type Culture Collection: H2452 (epithelial type) and MSTO-211H (biphasic type). The pemetrexed-resistant sublines derived from them were H2452/PEM and 211H/PEM. Pemetrexed-resistant lung adenocarcinoma lines PC-9/PEM and A549/PEM were also tested.
• Exposure: No asbestos exposure was studied; asbestos is mentioned only as background in the introduction. The cells were exposed to pemetrexed at concentrations increased from 10 nM to 3 μM over about 50 passages to create resistance. Resistant and parental cells were then treated with picropodophyllin (0.1 to 1.0 μM), vinorelbine, paclitaxel and other drugs, and with siRNA to knock down IGF-1R or TYMS.
• Main results:
  • Pemetrexed reduced the viability of the original (pemetrexed-naïve) MPM lines but not of the pemetrexed-resistant lines.
  • IGF1R and PDGFRB gene expression was higher in H2452/PEM cells than in H2452 cells. In 211H/PEM cells, expression of all receptor tyrosine kinase genes tested either decreased or stayed the same compared with 211H cells.
  • Picropodophyllin reduced the viability of both resistant MPM lines (H2452/PEM and 211H/PEM) more than that of their parental lines.
  • In the pemetrexed-resistant MPM cells, picropodophyllin caused caspase-independent cell death without causing DNA damage.
  • Knocking down IGF-1R with siRNA significantly decreased IGF-1Rβ expression but did not reduce the viability of H2452/PEM or 211H/PEM cells.
  • The authors reported that picropodophyllin killed the resistant MPM lines by inhibiting microtubule formation and not by IGF-1R inhibition alone. It caused abnormal mitotic spindles in H2452/PEM cells and multinucleation in 211H/PEM cells.
  • Picropodophyllin combined with vinorelbine had a synergistic effect in the pemetrexed-resistant MPM lines but not in the parental lines.
  • In 3-dimensional spheroid cultures, the pemetrexed-resistant lines were more sensitive to picropodophyllin than the parental lines.
• The authors' conclusion: The authors concluded that picropodophyllin may be more effective against MPM with acquired pemetrexed resistance than against pemetrexed-naïve MPM. They also concluded that vinorelbine can potentially be combined with picropodophyllin for such cases.
• Limitations the authors state:
  • Only two sets of parental and pemetrexed-resistant human MPM cell lines were used, which the authors said is not completely representative of acquired pemetrexed-resistant MPM.
  • No in vivo experiments were performed to determine the efficacy of picropodophyllin and vinorelbine alone or in combination.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Pleural Mesothelioma, Vinorelbine.

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• Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent — J.L. Hurwitz, I. Stasik, et al. (2012)
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