Abstract
(1) Background: Toad venom (Bufonis Venenum, known as ‘Chansu’ in Chinese), the secretion of the ear-side gland and skin gland of Bufo gargarizans cantor or Duttaphrynus melanostictus Schneider, has been utilized to treat several diseases in China for thousands of years. However, due to the chemical variability of the components, systematic chemical composition and the key pharmacophores in toad venom have not yet fully understood. Besides, it contains a variety of effective compounds with different physiological activity and chemotypes, mainly including alkaloids, bufogenins, bufotoxins, and so on. The recent pharmacological researches have demonstrated that several bufogenins have remarkable pharmacological effects, such as anti-inflammatory, analgesic effects, and anti-tumor effects. Aim of the study: To identify the bioactive compounds and pharmacophores originating from toad venom based on analyzing spectrum-effect relationship by chemometrics and to explore the anti-cancer mechanism primarily. (2) Materials and methods: Fingerprint of the 21 batches of samples was established using HPLC (High Performance Liquid Chromatography). The anti-tumor activity of extracts were determined by in-vitro assays. Chemometric analysis was used to establish the spectrum-effect model and screen for active ingredients. Pharmacodynamic tests for the screened active compound monomers were conducted with in-vitro assays. Further anti-tumor mechanisms were investigated using western blot and flow cytometry. (3) Results: The established spectrum-effect model has satisfactory fitting effect and predicting accuracy. The inhibitory effect of major screened compounds on lung carcinoma cells A549 were validated in vitro, demonstrating that arenobufagin, telocinobufogenin, and cinobufotalin had significant anti-tumor effects. Through further investigation of the mechanism by western blotting and flow cytometry, we elucidated that arenobufagin induces apoptosis in A549 cells with the enhanced expression of cleaved PARP (poly (ADP-ribose) polymerase). These results may provide valuable information for further structural modification of bufadienolides to treat lung cancer and a method for discovery of anti-tumor active compounds. Conclusions: Our research offers a more scientific method for screening the principal ingredients dominating the pharmacodynamic function. These screened compounds (arenobufagin, etc.) were proven to induce apoptosis by overactivation of the PARP-pathway, which may be utilized to make BRCA (breast cancer susceptibility gene) mutant cancer cells more vulnerable to DNA damaging agents and kill them.
Highlights
Lung cancer is one of the most common cancers in humans with high incidence and mortality rate.Non-Small Cell Lung Carcinoma (NSCLC), the most common form of lung cancer, comprises of Molecules 2020, 25, 4269; doi:10.3390/molecules25184269 www.mdpi.com/journal/moleculesMolecules 2020, 25, 4269 approximately 85% of all cases of lung cancer [1,2]
The HPLC fingerprints for 21 batches of toad venom samples are shown in Figure 1, which was matched by the Similarity Evaluation System for Chromatographic Fingerprints
The inhibitory effects of toad venom extracts on A549 cells were researched, and a spectrum-effect relationship analysis model was established with satisfactory fitting accuracy and forecasting precision, and utilized to screen the main bioactive components in toad venom extracts
Summary
Lung cancer is one of the most common cancers in humans with high incidence and mortality rate.Non-Small Cell Lung Carcinoma (NSCLC), the most common form of lung cancer, comprises of Molecules 2020, 25, 4269; doi:10.3390/molecules25184269 www.mdpi.com/journal/moleculesMolecules 2020, 25, 4269 approximately 85% of all cases of lung cancer [1,2]. Lung cancer is one of the most common cancers in humans with high incidence and mortality rate. Non-Small Cell Lung Carcinoma (NSCLC), the most common form of lung cancer, comprises of Molecules 2020, 25, 4269; doi:10.3390/molecules25184269 www.mdpi.com/journal/molecules. Molecules 2020, 25, 4269 approximately 85% of all cases of lung cancer [1,2]. The dried white secretion from the postauricular and skin glands of Bufo gargarizans cantor, is well known for treating many kinds of cancer [4]. The main efficacy of toad venom is in detoxification, as an analgesic, etc. The medicine currently used in clinical practice in China are mainly complexes that have originated from toad venom [6,7,8]
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