Synergistic anti-tumor effect of bullfrog sialic acid-binding lectin and pemetrexed in malignant mesothelioma

Our plain-English summary of Synergistic anti-tumor effect of bullfrog sialic acid-binding lectin and pemetrexed in malignant mesothelioma, by T. Satoh, T. Tatsuta, S. Sugawara, et al (Oncotarget, 2017).

The study

• Authors: T. Satoh, T. Tatsuta, S. Sugawara, A. Hara, M. Hosono
• Journal: Oncotarget
• Published: 2017;8(26):42466-42477
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive cancer with limited therapeutic options. Sialic acid-binding lectin isolated from Rana catesbeiana oocytes (cSBL) is a multifunctional protein with anti-cancer activity. The effects of pemetrexed, cisplatin, and cSBL were evaluated in mesothelioma and normal mesothelial cell lines. We evaluated cytotoxicity, apoptosis, caspase-3 cleavage and activation, cell proliferation, cell cycle arrest, and levels of cell cycle proteins in H28 cells treated with pemetrexed, cisplatin, and cSBL alone or in combination. Treatment with cSBL alone was cytotoxic to mesothelioma cells. The anti-cancer effect of cSBL was observed in a broader range of cell lines and exhibited greater cancer cell selectivity than pemetrexed or cisplatin. Combination treatment with pemetrexed + cSBL resulted in greater dose-dependent cytotoxicity than pemetrexed + cisplatin, the standard of care in mesothelioma. The synergistic effect of pemetrexed + cSBL was mediated by the cytostatic effect of pemetrexed and the cytotoxic effect of cSBL. It thus appears that cSBL has therapeutic potential for the treatment of mesothelioma.

In plain English

This was a laboratory study on cells grown in dishes. No patients or animals were treated; asbestos exposure was not studied. The authors tested a bullfrog-egg protein (sialic acid-binding lectin, cSBL) alongside the mesothelioma drugs pemetrexed and cisplatin. They used five mesothelioma cell lines (epithelioid, biphasic and sarcomatoid) and one non-malignant mesothelial line, MeT5A. At 20 µM, cSBL reduced MeT5A viability by only 40%. Its relative sensitivity values (selectivity for cancer cells over MeT5A cells) ranged from 9.48 to 247.02. These exceeded cisplatin's in all five mesothelioma lines and pemetrexed's in four; in MSTO cells, pemetrexed's was higher (465.99). cSBL was also toxic to drug-resistant cell lines. In the sarcomatoid H28 cells, pemetrexed plus cSBL and pemetrexed plus cisplatin reduced viability to a similar extent. Pemetrexed plus cSBL showed the stronger synergy, and cisplatin plus cSBL was weakest. The combinations did not significantly increase apoptosis (programmed cell death) compared with single treatments. Pemetrexed and cisplatin mainly halted cell division, while cSBL killed cells. The authors concluded that pemetrexed plus cSBL was comparable or even superior to pemetrexed plus cisplatin.

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) experiment on cultured human cell lines
• Who was studied: Five mesothelioma cell lines: epithelioid H2452, MESO-1 and MESO-4; biphasic MSTO; sarcomatoid H28. Also one non-malignant mesothelial cell line, MeT5A. Combination and mechanism experiments used H28 cells.
• Exposure: Treatment of cells with pemetrexed, cisplatin and cSBL (a protein from bullfrog oocytes), alone or in pairs. Mechanism experiments used 20 µM pemetrexed, 40 µM cisplatin and 1 µM cSBL for 72 hours. Asbestos exposure was not studied.
• Main results:
  • In non-malignant MeT5A cells, cSBL at 20 µM reduced viability by only 40%. The Results section calls 20 µM the highest concentration, but the Figure 1 caption gives a cSBL range up to 30 µM. By comparison, pemetrexed reduced MeT5A viability by 50% at 0.01 µM and cisplatin by 70% at 10 µM.
  • In the mesothelioma cell lines, the relative sensitivity (cancer-cell selectivity versus MeT5A cells) of cSBL ranged from 9.48 to 247.02. The Results text describes this as higher than the values for pemetrexed and cisplatin. In Table 1 it is higher than cisplatin's in all five lines and higher than pemetrexed's in four lines.
  • In MSTO cells, Table 1 gives a relative sensitivity of 465.99 for pemetrexed, which is higher than cSBL's 247.02 in the same cells.
  • H2452, MESO-1 and MESO-4 cells were resistant to pemetrexed (RS 0.37, 0.06 and 0.06). H28, H2452 and MESO-1 cells were resistant to cisplatin (RS 0.66, 0.24 and 0.26). cSBL was toxic to these drug-resistant cell lines.
  • In H28 cells, pemetrexed plus cisplatin and pemetrexed plus cSBL reduced cell viability to a similar extent.
  • In H28 cells, pemetrexed plus cSBL showed a stronger synergistic effect than the other combinations. Cisplatin plus cSBL showed the weakest cytotoxic and synergistic effects.
  • In H28 cells, the pemetrexed concentration predicted to reduce viability by 50% was 0.38 µM when combined with cSBL, compared with 0.65 µM when combined with cisplatin.
  • In H28 cells after 72 hours, the proportions of annexin V-positive (apoptotic) cells were 27.3% with pemetrexed, 38.7% with cisplatin and 44.3% with cSBL. With pemetrexed plus cisplatin, pemetrexed plus cSBL and cisplatin plus cSBL they were 44.8%, 47.3% and 46.0%. Differences between single and combination treatments were not statistically significant.
  • In H28 cells, caspase-3 activity did not differ significantly between cSBL alone and the combination treatments. In the Caspase-Glo assay, pemetrexed and cisplatin alone did not induce caspase-3 activation.
  • Compared with control cells at 72 hours, total H28 cell numbers fell by 10.4% with pemetrexed, 14.2% with cisplatin and 32.7% with cSBL. Dead cells increased significantly only with cSBL.
  • In H28 cells, pemetrexed caused cell cycle arrest in S phase and cisplatin in S or G2 phase. cSBL had a minimal effect on the cell cycle but increased sub-G1 cells, a sign of apoptosis.
• The authors' conclusion: The authors concluded the following. In these cell lines, pemetrexed plus cSBL had a strong synergistic effect that was comparable or even superior to standard pemetrexed plus cisplatin. They proposed that this comes from the cytostatic (growth-halting) effect of pemetrexed combined with the cytotoxic (cell-killing) effect of cSBL, and that cSBL has therapeutic potential for mesothelioma.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Mesothelioma, Cisplatin, Mesothelial Cells, Apoptosis, Synergistic Effect.

Related studies

• Transcriptomic alterations in malignant pleural mesothelioma cells in response to long‑term treatment with bullfrog sialic acid‑binding lectin — T. Tatsuta, A. Nakasato, et al. (2021)
• Sialic acid-binding lectin from bullfrog eggs inhibits human malignant mesothelioma cell growth in vitro and in vivo — T. Tatsuta, T. Satoh, et al. (2018)
• Sialic acid-binding lectin (leczyme) induces apoptosis to malignant mesothelioma and exerts synergistic antitumor effects with TRAIL — T. Tatsuta, M. Hosono, et al. (2014)
• Interferon-β produces synergistic combinatory anti-tumor effects with cisplatin or pemetrexed on mesothelioma cells — Q. Li, K. Kawamura, et al. (2013)
• Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels — S. Okamoto, Y. Jiang, et al. (2013)
• Sialic acid mediates the initial binding of positively charged inorganic particles to alveolar macrophage membranes — J.E. Gallagher, G. George, et al. (1987)

Browse more research in Oncotarget, or return to medical research.