Combined use of irinotecan and p53 activator enhances growth inhibition of mesothelioma cells

Our plain-English summary of Combined use of irinotecan and p53 activator enhances growth inhibition of mesothelioma cells, by B. Han, H.C. Lee-Okada, M. Ishimine, et al (FEBS Open Bio, 2020).

The study

• Authors: B. Han, H.C. Lee-Okada, M. Ishimine, H. Orita, K. Nishikawa, T. Takagaki, K. Kajino, T. Yokomizo, O. Hino, T. Kobayashi
• Journal: FEBS Open Bio
• Published: 2020;10(11):2375-2387
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is an aggressive malignant neoplasm which rapidly invades pleural tissues and has a poor prognosis. Here, we explore enhancement of the effect of irinotecan [camptothecin-11 (CPT-11)] by the p53-dependent induction of carboxylesterase 2 (CES2), a CPT-11-activating enzyme, in MM. The level of CES2 mRNA was greatly increased on treatment with nutlin-3a. A combination of CPT-11 and nutlin-3a inhibited the growth of MM cells more effectively than either drug alone. Knocking down CES2 in MM cells reduced the effect of the drug combination, and its forced expression in MESO4 cells enhanced the growth inhibitory activity of CPT-11 in the absence of nutlin-3a. Enhancement of the growth inhibitory activity of CPT-11 by nutlin-3a suggests a possible new combinatorial MM chemotherapy regimen.

© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

In plain English

This laboratory study tested drugs on four human malignant mesothelioma cell lines, not on patients. Three lines (MESO4, 211H and H28) had normal (wild-type) p53, a tumor-suppressor protein; one (MESO1) had lost it. The authors asked whether nutlin-3a, a p53-activating drug, could boost irinotecan (CPT-11), a chemotherapy drug that the enzyme CES2 converts into its active form. Nutlin-3a raised CES2 levels in the three p53-normal lines, but only minimally in MESO1. In MESO4 cells, adding nutlin-3a lowered the irinotecan concentration needed to halve growth from 54.85 µg/ml (95% CI 50.82 to 59.59) to 34.19 µg/ml (95% CI 28.69 to 41.7). The combination also inhibited growth more than either drug alone in H28 cells, only slightly in 211H cells, and not at all in MESO1. Blocking CES2 partly reduced the combined effect. MESO4 cells engineered to make extra CES2 responded more to irinotecan alone. The authors concluded that nutlin-3a's raising of CES2 explained the combined effect at least in part, and speculated that other effects contributed. They noted that how p53 raises CES2 in mesothelioma is still unclear.

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 of human malignant mesothelioma cell lines grown in culture
• Who was studied: Four human malignant mesothelioma cell lines: ACC-MESO-1 (MESO1) and ACC-MESO-4 (MESO4) from the RIKEN cell bank, Japan, and MSTO-211H (211H) and NCI-H28 (H28) from the American Type Culture Collection. MESO4, 211H and H28 express wild-type p53; MESO1 has TP53 loss.
• Exposure: Drug treatments, not asbestos: irinotecan (CPT-11), the p53 activator nutlin-3a, doxorubicin, and SN-38 (the active form of irinotecan), alone and in combination. CES2 was also reduced by RNA interference or increased by forced expression.
• Main results:
  • Nutlin-3a and doxorubicin each significantly suppressed growth of MESO4 and 211H cells. They tended to suppress H28 growth, but the doxorubicin effect in H28 was not statistically significant. Neither drug appreciably suppressed MESO1.
  • Nutlin-3a and doxorubicin induced CES2, CDKN1A and NOXA expression in MESO4, 211H and H28 cells. Induction in MESO1 was minimal.
  • In MESO4 cells, irinotecan alone at 20 µg/ml inhibited growth by about 15% to 25% after 48 hours.
  • In MESO4 cells, nutlin-3a lowered the IC50 of irinotecan 1.6-fold: from 54.85 µg/ml (95% CI 50.82 to 59.59 µg/ml) to 34.19 µg/ml (95% CI 28.69 to 41.7 µg/ml).
  • The combined growth-inhibiting effect of nutlin-3a and irinotecan was also seen in H28 cells.
  • The combined effect was only slight in 211H cells, which the authors attribute possibly to their high sensitivity to irinotecan alone.
  • No combined effect was seen in MESO1 cells.
  • Compared with either drug alone, the combination increased cell death in H28 and 211H cells.
  • Reducing CES2 with siRNA in MESO4 cells only partly suppressed the growth-inhibiting effect of the combination.
  • MESO4 cells engineered to overexpress CES2 showed greater growth suppression with irinotecan alone than control cell lines.
• The authors' conclusion: The authors concluded that the combined effect of irinotecan and nutlin-3a in mesothelioma cells was achieved, at least in part, through nutlin-3a's induction of CES2, the enzyme that converts irinotecan to its active metabolite SN-38.
• Limitations the authors state:
  • Blocking CES2 by RNA interference only partly reversed the combined effect.
  • The authors speculate that the combined effect is not limited to CES2 upregulation.
  • The mechanism by which p53 raises CES2 in mesothelioma remains unclear.
  • Adverse events caused by the p53 activator itself would need to be considered.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Neoplasm, Prognosis, Chemotherapy.

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