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

Satoh, Toshiyuki; Tatsuta, Takeo; Sugawara, Shigeki; Hara, Akiyoshi; Hosono, Masahiro

doi:10.18632/oncotarget.17198

Cited by 12 publications

(14 citation statements)

References 49 publications

(50 reference statements)

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“…We found that MPM cell lines could be categorized into two groups according to their susceptibility to pemetrexed treatment. In agreement with previous findings ( Satoh et al, 2017 ), the NCI-H2452 cell line was resistant to pemetrexed treatment as compared to other MPM cell lines. MSTO-211H was highly sensitive to pemetrexed in the nanomolar range as compared to the pemetrexed-resistant cell line NCI-H2452 ( Figure 1 ).…”

Section: Resultssupporting

confidence: 93%

Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells

et al. 2018

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Antifolates are a class of drugs effective for treating malignant pleural mesothelioma (MPM). The majority of antifolates inhibit enzymes involved in purine and pyrimidine synthesis such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and glycinamide ribonucleotide formyltransferase (GART). In order to select the most suitable patients for effective therapy with drugs targeting specific metabolic pathways, there is a need for better predictive metabolic biomarkers. Antifolates can alter global metabolic pathways in MPM cells, yet the metabolic profile of treated cells has not yet been clearly elucidated. Here we found that MPM cell lines could be categorized into two groups according to their sensitivity or resistance to pemetrexed treatment. We show that pemetrexed susceptibility could be reversed and DNA synthesis rescued in drug-treated cells by the exogenous addition of the nucleotide precursors hypoxanthine and thymidine (HT). We observed that the expression of pemetrexed-targeted enzymes in resistant MPM cells was quantitatively lower than that seen in pemetrexed-sensitive cells. Metabolomic analysis revealed that glycine and choline, which are involved in one-carbon metabolism, were altered after drug treatment in pemetrexed-sensitive but not resistant MPM cells. The addition of HT upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive MPM cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, and points to potential biomarkers for informing clinical decisions regarding the most effective therapies for patients with MPM.

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Section: Resultssupporting

confidence: 93%

Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells

et al. 2018

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“…Pharmacological interactions between these three agents were investigated by evaluating the viability of H2452 and MSTO cells treated with pemetrexed + cisplatin, cSBL + pemetrexed, and cSBL + cisplatin. The drug concentration in each combination regimen was based on the IC 50 value for each agent previously determined via single treatments [ 35 ]. The viability curves for each drug in single or combination treatments are presented in Fig 5 .…”

Section: Resultsmentioning

confidence: 99%

“…The RNase activity was also determined to be critical for apoptosis induction in MDA-MB231 human breast cancer cells, as an amino acid-replaced mutant of cSBL that lacked RNase activity did not exhibit the apoptosis-inducing effect, even when internalized into the cells like native cSBL [ 33 ]. The efficacy of cSBL on malignant mesothelioma cells has previously been reported [ 34 , 35 ]; Even though cSBL hardly show cytotoxicity to normal mesothelial cell Met5A, it efficiently reduced the viability of H28 malignant mesothelioma cells, and exhibited synergistic effects with TRAIL and pemetrexed on these cells.…”

Section: Introductionmentioning

confidence: 86%

“…Cells (5×10 4 cells/mL) were cultured in 96-well plates (100 μL/well). The concentration of pemetrexed, cisplatin, or cSBL was based on the IC 50 values obtained in the single-treatment experiments conducted in our prior study [ 35 ]. After 72 h, the cells were incubated with Cell Count Reagent SF (Nacalai Tesque Inc., Kyoto, Japan) at 37°C in a 5% CO 2 atmosphere for 1–4 h. The absorbance of the resulting product at 450 nm was measured, and the background absorbance at 650 nm was subtracted.…”

Section: Methodsmentioning

confidence: 99%

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Sialic acid-binding lectin from bullfrog eggs inhibits human malignant mesothelioma cell growth in vitro and in vivo

et al. 2018

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Malignant mesothelioma is an aggressive cancer that results from exposure to asbestos. The therapeutic options for this type of cancer are limited; therefore, the development of novel therapeutic agents is urgently required. Sialic acid-binding lectin isolated from Rana catesbeiana oocytes (cSBL) is a novel therapeutic candidate for cancer, which exhibits antitumor activity mediated through RNA degradation. In the present study, we evaluated the effect of cSBL in vitro and in vivo. Xenograft-competent H2452 and MSTO human mesothelioma cell lines were treated with cSBL, and the pathway by which cSBL induces apoptosis was analyzed. In vivo studies were performed using nude mice inoculated with one of the two cell lines, and the effects of cSBL and pemetrexed were monitored simultaneously. Furthermore, the pharmacological interactions between the three agents (pemetrexed, cisplatin and cSBL) were statistically assessed. It was demonstrated that cSBL treatments caused morphological and biochemical apoptotic changes in both cell lines. Caspase cascade analysis revealed that an intrinsic pathway mediated cSBL-induced apoptosis. The administration of cSBL significantly inhibited tumor growth in two xenograft models, without any adverse effects. Furthermore, the combination index and dose reduction index values indicated that the cSBL + pemetrexed combination showed the highest synergism, and thus potential for reducing dosage of each drug, compared with the other combinations, including the existing pemetrexed + cisplatin regimen. cSBL exerted prominent antitumor effects on malignant mesothelioma cells in vitro and in vivo, and showed favorable effects when combined with pemetrexed. These results suggest that cSBL has potential as a novel drug for the treatment of malignant mesothelioma.

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“…The antagonism is probably due to the opposite modulation of the tumor suppressor p21 by the two compounds. If cisplatin sharply increases p21 expression, SBLc antagonizes it, resulting in a lack of synergy [112]. In the case of SBLc plus TNF-related apoptosis-inducing ligand, a synergistic effect on H28 cells has been recorded, probably caused by an enhancement in the cleavage of the proapoptotic protein Bid that reinforces caspase activation [110].…”

Section: Rana Catesbeianamentioning

confidence: 99%

Antitumor Potential of Marine and Freshwater Lectins

et al. 2019

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Often, even the most effective antineoplastic drugs currently used in clinic do not efficiently allow complete healing due to the related toxicity. The reason for the toxicity lies in the lack of selectivity for cancer cells of the vast majority of anticancer agents. Thus, the need for new potent anticancer compounds characterized by a better toxicological profile is compelling. Lectins belong to a particular class of non-immunogenic glycoproteins and have the characteristics to selectively bind specific sugar sequences on the surface of cells. This property is exploited to exclusively bind cancer cells and exert antitumor activity through the induction of different forms of regulated cell death and the inhibition of cancer cell proliferation. Thanks to the extraordinary biodiversity, marine environments represent a unique source of active natural compounds with anticancer potential. Several marine and freshwater organisms, ranging from the simplest alga to the most complex vertebrate, are amazingly enriched in these proteins. Remarkably, all studies gathered in this review show the impressive anticancer effect of each studied marine lectin combined with irrelevant toxicity in vitro and in vivo and pave the way to design clinical trials to assess the real antineoplastic potential of these promising proteins. It provides a concise and precise description of the experimental results, their interpretation as well as the experimental conclusions that can be drawn.

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

Cited by 12 publications

References 49 publications

Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells

Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells

Sialic acid-binding lectin from bullfrog eggs inhibits human malignant mesothelioma cell growth in vitro and in vivo

Antitumor Potential of Marine and Freshwater Lectins

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