Quinacrine Has Preferential Anticancer Effects on Mesothelioma Cells With Inactivating NF2 Mutations

Our plain-English summary of Quinacrine Has Preferential Anticancer Effects on Mesothelioma Cells With Inactivating NF2 Mutations, by D.B. Oien, S. Sarkar Bhattacharya, J. Chien, et al (Frontiers in Pharmacology, 2021).

The study

• Authors: D.B. Oien, S. Sarkar Bhattacharya, J. Chien, J. Molina, V. Shridhar
• Journal: Frontiers in Pharmacology
• Published: 2021;12:750352
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a rare cancer with disproportionately higher death rates for shipping and mining populations. These patients have few treatment options, which can be partially attributed to limited chemotherapy responses for tumors. We initially hypothesized that quinacrine could be combined with cisplatin or pemetrexed to synergistically eliminate mesothelioma cells. The combination with cisplatin resulted in synergistic cell death and the combination with pemetrexed was not synergistic, although novel artificially-generated pemetrexed-resistant cells were more sensitive to quinacrine. Unexpectedly, we discovered cells with NF2 mutations were very sensitive to quinacrine. This change of quinacrine sensitivity was confirmed by NF2 ectopic expression and knockdown in NF2 mutant and wildtype cell lines, respectively. There are few common mutations in mesothelioma and inactivating NF2 mutations are present in up to 60% of these tumors. We found quinacrine alters the expression of over 3000 genes in NF2-mutated cells that were significantly different than quinacrine-induced changes in NF2 wildtype cells. Changes to NF2/hippo pathway biomarkers were validated at the mRNA and protein levels. Additionally, quinacrine induces a G1 phase cell cycle arrest in NF2-mutated cells versus the S phase arrest in NF2-wildtype cells. This study suggests quinacrine may have repurposing potential for a large subset of mesothelioma patients.

Copyright © 2021 Oien, Sarkar Bhattacharya, Chien, Molina and Shridhar.

In plain English

This was a laboratory study of mesothelioma cells grown in dishes. It did not study patients or asbestos exposure. The authors tested the drug quinacrine on human pleural mesothelioma cell lines, alone and with the chemotherapy drugs cisplatin and pemetrexed. Cells made resistant to pemetrexed became more sensitive to quinacrine: the concentration producing 50% inhibition fell 55.8% in one line and 38.0% in another. Cisplatin-resistant cells showed no significant change. Quinacrine with cisplatin gave average combination index values of 0.68 to 0.75, which the authors interpreted as moderate synergy. Quinacrine with pemetrexed was not synergistic. Cell lines with mutations in the NF2 gene were the most sensitive. Restoring NF2 in two such lines raised that concentration 4.9- and 2.6-fold. Silencing NF2 in two other lines lowered it by 81.7% and 82.0%. In NF2-mutated cells, quinacrine changed gene activity differently, including in the hippo pathway, and halted the cells at a different stage of division. The authors concluded that quinacrine has repurposing potential, but said its effect in patients' tumors still needs to be assessed.

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) study using cultured cancer cell lines
• Who was studied: Human malignant pleural mesothelioma cell lines (H28, H226, H2052, H2452, H2591). Also a lung cancer line (A549), a non-malignant mesothelium line (Met-5A), and a mouse mesothelioma line (AE17). No human subjects.
• Exposure: Drug treatments: quinacrine alone and combined with cisplatin or pemetrexed. Asbestos exposure was not studied, although the mouse AE17 cell line was originally derived from mice injected with crocidolite asbestos fibers.
• Main results:
  • H2452 cells made pemetrexed-resistant (P452): the quinacrine IC50 (concentration producing 50% inhibition) fell 55.8%, from 3.46 to 1.53 µM. Cisplatin-resistant H2452 cells showed no significant change.
  • H226 cells made pemetrexed-resistant (P226): the quinacrine IC50 fell 38.0%, from 1.84 to 1.14 µM. Cisplatin-resistant H226 cells showed no significant change.
  • Quinacrine with cisplatin gave average combination index values of 0.68 to 0.75 in H2052, H226 and H2452 cells, interpreted as moderate synergism. The discussion describes this as a moderately synergistic response for H2452 and H226, and for some combinations in H2052.
  • Quinacrine with pemetrexed was not synergistic (data not shown).
  • The largest drops in quinacrine IC50 were in the NF2-mutated lines H2591, H2052 and H226.
  • Restoring wildtype NF2 in the NF2-mutated lines H2591 and H2052 increased the quinacrine IC50 4.9-fold and 2.6-fold.
  • Silencing NF2 in the NF2-wildtype lines H2452 and H28 decreased the quinacrine IC50 by 81.7% and 82.0%.
  • RNA sequencing found 3168 genes whose response to quinacrine differed between NF2-mutated lines (H2591, H2052) and NF2-wildtype lines (H2452, H28).
  • The authors interpreted the gene-expression analyses as evidence that quinacrine perturbs the hippo pathway in NF2-mutated cells.
  • Quinacrine increased the share of cells in the G1 phase in the NF2-mutated lines H2591 and H2052. It caused an S-phase arrest in an NF2-wildtype line (printed as H2542).
  • Quinacrine at 5 and 10 µM for 4 hours raised reactive oxygen species in all 4 cell lines tested, with the largest increases in H2591 and H2052.
• The authors' conclusion: The authors concluded that quinacrine has repurposing potential for mesothelioma with NF2 mutations or chemotherapy resistance, and as an adjuvant treatment.
• Limitations the authors state:
  • The findings come from cells in the laboratory; whether quinacrine works in patients' tumors still needs to be assessed.
  • The direct target of quinacrine that acts on the YAP/hippo pathway is not known.
  • It is unknown whether the cells with NF2 restored or silenced would show the same overall gene-expression response as the NF2-mutated lines.
  • H226 was left out of most later experiments because the biological effect of its NF2 alteration was unclear.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Chemotherapy, Cisplatin, Pemetrexed (Alimta), Biomarker.

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