Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpeneSO1861

Abstract

Targeted cancer therapy provides the basis for the arrest of tumor growth in aggressive pancreatic carcinoma; however, a number of protein‐based targeted toxins lack efficacy due to insufficient endosomal escape after being endocytosed. Therefore, we tested a fusion protein of the ribosome‐inactivating protein dianthin and human epidermal growth factor in combination with a glycosylated triterpene (SO1861) that serves as an endosomal escape enhancer. In vitro investigations with the pancreatic carcinoma cell lines BxPC‐3 and MIA PaCa‐2 revealed no significant differences to off‐target cells in the half maximal inhibitory concentration (IC 50) for the fusion protein. In contrast, combination with SO1861 decreased the IC 50 for BxPC‐3 cells from 100 to 0.17 nm, whereas control cells remained unaffected. Monotherapy of BxPC‐3 xenografts in CD‐1 nude mice led to a 51.7% average reduction in tumor size (40.8 mm3) when compared to placebo; however, combined treatment with SO1861 resulted in a more than 13‐fold better efficacy (3.0 mm3 average tumor size) with complete regression in 80% of cases. Immunohistochemical analyses showed that tumor cells with lower target receptor expression are, in contrast to the combination therapy, able to escape from the monotherapy, which finally results in tumor growth. At the effective concentration, we did not observe liver toxicity and saw no other side effects with the exception of a reversible skin hardening at the SO1861 injection site, alongside an increase in platelet counts, plateletcrit, and platelet distribution width. In conclusion, combining a targeted toxin with SO1861 is proven to be a very promising approach for pancreatic cancer treatment.

Glycosylated Triterpenoids as Endosomal Escape Enhancers in Targeted Tumor Therapies

“…Triterpene saponins and saponin containing fractions are usually analyzed by high performance thin layer chromatography, thin layer chromatography-densitometry [ 52 ], infrared spectroscopy, and liquid chromatography coupled to (tandem) mass spectrometry. Tandem mass spectrometry is an indispensable tool that provides important structural information.…”

Introduction of Dianthins: A New Promising Horizon Toward Continuous Research on Breast Cancer Bulldozing in Iran

“…Referring to previous studies, it is well established that Dianthin 30 has cytotoxic activity [16][17][18]. The cytotoxicity of the toxin has been evaluated on different cell lines as Hodgkins' Lymphoma cells (infusion with anti-CD30, IC50: 162 pg-50ng), human pancreatic carcinoma cell lines BxPC-3 (IC50: 10µg), MIA PaCa-2 (IC50: 100ng), NIH-3T3 mouse embryonic fibroblast cells (IC50: 22ng ), and Jurkat cells (IC50: 21ng) [16].…”

Dianthin and Its Potential in Targeted Tumor Therapies

“…Pancreas and lung did not show any morphological alterations [73]. The same combination of dianthin-30-EGF and SO1861 was used for the treatment of pancreatic BxPC-3 cell carcinoma in nude mice [71]. Monotherapy with dianthin-30-EGF in the absence of SO1861 resulted on average in a 52% reduction of the tumor volume and no complete regression was observed (three mice had retarded tumor growth and two had continuous tumor growth).…”

“…Monotherapy with dianthin-30-EGF in the absence of SO1861 resulted on average in a 52% reduction of the tumor volume and no complete regression was observed (three mice had retarded tumor growth and two had continuous tumor growth). However, in the presence of SO1861, the tumor volume was reduced on average by 97% and four out of five mice showed complete regression [71]. Complete blood count analysis did not show suspicious values with the exception of increased platelet count.…”

“…Complete blood count analysis did not show suspicious values with the exception of increased platelet count. At the injection site of SO1861, skin hardening was noticed after two therapy cycles, but no skin lesions were observed at the injection site and at the tumor site after six therapy cycles, indicating recovery [71]. Further animal studies with dianthin as the active pharmaceutic agent are required to corroborate its potential role as a cancer cell-killing protein in targeting tumor therapies.…”