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

Abstract

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.

Antitumor Potential of Marine and Freshwater Lectins

“…SBLc alone was effective on cisplatin-and pemetrexate-resistant MESO-1 and MESO-4 cells (Table 3). Moreover, it synergistically increased the antitumor activity of pemetrexate in H28 [138] and MSTO cells [113] (Table 3) with an even stronger effect than that of pemetrexed plus cisplatin. The association of pemetrexed plus SBLs was particularly effective, because the first one blocks the proliferation of cells, which will be then easily killed thanks to the cytotoxic effect of the second one [113].…”

“…In other words, as Aristotle would suggest, in medio stat virtus. When inside the cell, SBLc activates the intrinsic apoptotic pathway on more than 30 tumor cell lines representing leukemia [107][108][109]118,120,131,132], Burkitt's lymphoma [108,109], cervical [133], hepatocellular [120,121,133], and estrogen-positive and -negative breast carcinomas [113,114,116,117,120], glioblastoma [119], and malignant mesothelioma [110,113] (Table 3).…”

“…The expression of ER, progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) represents the groundwork for the classification of this type of cancer and is useful for prognostic prediction and therapy selection. Usually, the worst prognosis refers to triple negative cancer (ER, PR and HER negative) and to those tumors overexpressing HER2 together with the epidermal growth factor (EGFR) [113]. Different studies about SBLc antitumor ability showed different results on the same tumor types.…”

“…Already in 1994, Nitta et al [107] demonstrated the ability of SBLc to counteract sarcoma 180 cells inoculated on mice (Table 3) with doses at least 150 times lower than the lethal ones. More, SBLc suppressed mesothelioma (H2452 or MSTO cells) growth in xenografted nude mice, without causing toxicity nor body weight changes [113]. For the record, pemetrexed, which is one of the drugs of choice currently used for the cure of mesothelioma, failed to eradicate murine MSTO-xenografted tumors on the same experimental conditions [113].…”

“…More, SBLc suppressed mesothelioma (H2452 or MSTO cells) growth in xenografted nude mice, without causing toxicity nor body weight changes [113]. For the record, pemetrexed, which is one of the drugs of choice currently used for the cure of mesothelioma, failed to eradicate murine MSTO-xenografted tumors on the same experimental conditions [113]. In addition, SBLc effectively inhibited the growth of glioblastoma tumors in nude mice once again without causing any side effect [119].…”