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. 2022 Feb 23;41:75. doi: 10.1186/s13046-022-02284-7

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 1 — Cisplatin and MLN4924 combination induce mesothelioma cell death. Primary MPM cells derived from 3 different histopathological subtypes, epithelioid (EPI BAP1⁺ UPN7 and EPI BAP1^- UPN11), biphasic (BIP BAP1⁺ UPN14 and BIP BAP1^- UPN16) and sarcomatous (SAR BAP1⁺ UPN22 and SAR BAP1^- UPN23), were incubated 48 h in fresh medium (CTRL), with 50 μM cisplatin (PT), 0.2 μM MLN4924 (MLN) or their combination (PT+MLN). A. LDH release was measured spectrophotometrically in triplicates. Data are presented as means of 2 primary MPM for each histopathological subtype used + SD (n = 3). ***p < 0.001: treated cells vs CTRL cells; °°°p < 0.001: PT+MLN-treated cells vs PT-treated cells. B. Representative crystal violet staining of epithelioid (EPI; UPN7), biphasic (BIP; UPN16) and sarcomatous (SAR; UPN22) MPM cells. The photographs are representative of 1 out of 3 experiments, performed in quadruplicates. C. Crystal violet quantification after incubation for 72 h in fresh medium (CTRL), with 50 μM cisplatin (PT), 0.2 μM MLN4924 (MLN) or their combination (PT+MLN) of epithelioid (EPI BAP1⁺ UPN7 and EPI BAP1^- UPN11), biphasic (BIP BAP1⁺ UPN14 and BIP BAP1^- UPN16) and sarcomatous (SAR BAP1⁺ UPN22 and SAR BAP^- UPN23) MPM cells. Data are presented as means of 2 primary MPM for each histopathological subtype used + SD (n = 3), performed in quadruplicates. ***p < 0.001: treated cells vs CTRL cells; °°°p < 0.001: PT+MLN-treated cells vs PT -treated cells. D. AB1 cells were subcutaneously implanted into 6-week-old female BALB/c mice, when the tumor size reached 50 mm³ mice (n = 10 animals/group) were treated for 3 consecutive weeks as indicated in the Methods section. Upper panel: Tumor growth was monitored twice a week by caliber measurement. Data are presented as means ± SD. *p < 0.05, **p < 0.01: all groups vs CTRL group; °p < 0.05: PT+MLN group vs PT group. Lower panel: Representative photographs of tumors from each group. E. Epithelioid (EPI BAP1⁺ UPN7), biphasic (BIP BAP1⁺ UPN14) and sarcomatous (SAR BAP1⁺ UPN22) cells, i.e. one MPM representative per each histotype, were incubated with scalar concentrations (0, 10^-10, 10^-9, 10^-8, 10^-7, 10^-6, 10^-5, 10^-4, 10^-3 M) of MLN4924 and cisplatin for 72 h, then the viability was assessed by the crystal violet staining. The Combination Index (CI) was calculated using the CalcuSyn software. Results are representative of 3 independent experiments, performed in quadruplicates. ED50: dose that effectively reduces cell viability at 50% with single agent or their combination