Anticancer agent α-sulfoquinovosyl-acylpropanediol enhances the radiosensitivity of human malignant mesothelioma in nude mouse models

Our plain-English summary of Anticancer agent α-sulfoquinovosyl-acylpropanediol enhances the radiosensitivity of human malignant mesothelioma in nude mouse models, by E. Inamasu, T. Tsuchiya, M. Yamauchi, et al (Journal of Radiation Research, 2022).

The study

• Authors: E. Inamasu, T. Tsuchiya, M. Yamauchi, K. Nishi, K. Matsuda, F. Sugawara, K. Sakaguchi, R. Mori, K. Matsumoto, T. Miyazaki, G. Hatachi, R. Doi, H. Watanabe, K. Tomoshige, N. Matsuda, Y. Higami, I. Shimokawa, M. Nakashima, T. Nagayasu
• Journal: Journal of Radiation Research
• Published: 2022;63(1):19-29
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a highly malignant disease that develops after asbestos exposure. Although the number of MPM cases is predicted to increase, no effective standard therapies have been established. The novel radiosensitizer α-sulfoquinovosyl-acylpropanediol (SQAP) enhances the effects of γ-radiation in human lung and prostate cancer cell lines and in animal models. In this study, we explored the radiosensitizing effect of SQAP and its mechanisms in MPM. The human MPM cell lines MSTO-211H and MESO-4 were implanted subcutaneously into the backs and thoracic cavities of immunodeficient KSN/Slc mice, then 2 mg/kg SQAP was intravenously administered with or without irradiation with a total body dose of 8 Gy. In both the orthotopic and ectopic xenograft murine models, the combination of irradiation plus SQAP delayed the implanted human MSTO-211H tumor growth. The analysis of the changes in the relative tumor volume of the MSTO-211H indicated a statistically significant difference after 8 Gy total body combined with 2 mg/kg SQAP, compared to both the untreated control (P = 0.0127) and the radiation treatment alone (P = 0.0171). After the treatment in each case, immunostaining of the harvested tumors revealed decreased cell proliferation, increased apoptosis and normalization of tumor blood vessels in the SQAP- and irradiation-treated group. Furthermore, hypoxia-inducible factor (HIF) 1 mRNA and protein expression were decreased, indicating reoxygenation in this group. In conclusion, SQAP improved hypoxic conditions in tumor tissue and may elicit a radiosensitizing effect in malignant mesothelioma models.

© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.

In plain English

This was a mouse experiment testing a treatment. It did not study asbestos exposure. The authors implanted two human malignant pleural mesothelioma cell lines into male nude mice, either under the skin of the back or into the chest cavity: MSTO-211H (biphasic type) and MESO-4 (epithelioid type). Mice received the experimental drug SQAP (2 mg/kg into a vein on days 0 to 4), whole-body radiation (2 or 4 Gy on days 0 and 3), both, or neither. In mice with MSTO-211H tumors in the chest, SQAP plus 4 Gy radiation improved survival compared with untreated mice (p = 0.0143, 3 or 4 mice per group). In mice with MSTO-211H tumors under the skin, the combination slowed tumor growth more than radiation alone (P < 0.0171) and more than no treatment (P = 0.0127). For MESO-4, growth curves for the combination and for radiation alone overlapped. Combination-treated MSTO-211H tumors had fewer dividing cells, more dying cells (64.9% versus 15.1% in controls), more normal-looking blood vessels and less HIF1α, a marker of low oxygen. The authors concluded that SQAP with radiation suppressed mesothelioma growth in mice, especially the radiation-resistant biphasic type.

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: Animal experiment (human mesothelioma cell lines implanted into mice under the skin and into the chest cavity), with preliminary laboratory cell-culture radiation tests
• Who was studied: Five- to eight-week-old male nude mice (KSN/Slc) implanted with the human malignant pleural mesothelioma cell lines MSTO-211H (biphasic type) or MESO-4 (epithelioid type). Under-the-skin groups: for MSTO-211H, six, eight, nine and seven mice (control, SQAP, radiation, SQAP plus radiation) per the Methods; for MESO-4, four mice per group. Chest-cavity treatment groups had 3 or 4 mice each. Study done at Nagasaki University, Japan.
• Exposure: Treatment, not asbestos: SQAP (2 mg/kg per day by vein, days 0 to 4) given alone, with whole-body radiation (4 Gy per day on days 0 and 3, or 2 Gy per day in one chest-cavity experiment), radiation alone, or saline control
• Main results:
  • In laboratory dishes, the radiation sensitivity of the MSTO-211H and MESO-4 cell lines was very similar
  • Untreated mice with MSTO-211H cells in the chest cavity died within 40 days (50% survival time 37 days). Mice with MESO-4 cells survived more than 100 days (50% survival time 128 days).
  • In mice with MSTO-211H tumors in the chest cavity, SQAP plus 4 Gy radiation (days 0 and 3) improved survival compared with controls (p = 0.0143). The other comparisons were not statistically significant.
  • In mice with MSTO-211H tumors under the skin, tumor growth was inhibited significantly more with SQAP plus radiation than with radiation alone (P < 0.0171)
  • For MSTO-211H tumors under the skin, relative tumor volume after 8 Gy total plus 2 mg/kg SQAP also differed significantly from untreated controls (P = 0.0127), as stated in the article's abstract
  • In mice with MESO-4 tumors under the skin, the tumor growth curves for SQAP plus radiation and radiation alone overlapped
  • In harvested MSTO-211H tumors, Ki-67-positive (dividing) cells were significantly fewer in the SQAP plus radiation group than in the other groups
  • Average rates of TUNEL-positive (apoptotic, or dying) cells in MSTO-211H tumors were 15.1%, 21.9%, 19.6% and 64.9% in the control, SQAP, radiation and SQAP plus radiation groups
  • Average vascular normalization index ratios in MSTO-211H tumors were 0.16, 0.10, 0.10 and 0.43 in the control, SQAP, radiation and SQAP plus radiation groups (P < 0.001)
  • HIF1α staining showed significantly fewer hypoxic (low-oxygen) cells in the SQAP plus radiation group (P < 0.001)
  • HIF1α mRNA was significantly lower in the SQAP plus radiation group (P = 0.0287)
  • Body weights were unchanged in all groups (data not shown)
• The authors' conclusion: The authors concluded that SQAP with radiation suppressed malignant pleural mesothelioma tumor growth in mouse models, especially in radiation-resistant biphasic-type mesothelioma. They suggested that reduced HIF1α activity with vascular normalization might be the mechanism, and that SQAP should be applied in clinical trials.
• Limitations the authors state:
  • The authors did not analyze focal adhesion kinase (FAK), a protein that SQAP binds to and that may underlie its effect

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Apoptosis, Hypoxia.

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