Antineoplastic Activity of Monocrotaline Against Hepatocellular Carcinoma

Kusuma, Sandeep Solmon; Tanneeru, Karunakar; Didla, Swroopa; Devendra, Bellary Nagaraju; Patnala, Kiranmayi

doi:10.2174/1871520614666140715085907

Cited by 8 publications

(6 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the in vitro assay with rat primary hepatocytes, the IC 50 value of monocroaline was 20.7- and 35.7-fold higher than the IC 50 values previously reported in the same model system for lasiocarpine and riddelliine, respectively (Chen et al 2018 ). The lower toxicity of monocrotaline in in vitro liver model systems is also in line with what has been observed in other studies using HepG2 or HepaRG cells (Kusuma et al 2014 ; Louisse et al 2019 ).…”

Section: Discussionsupporting

confidence: 91%

Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach

2020

View full text Add to dashboard Cite

The aim of the present study was to use an in vitro-in silico approach to predict the in vivo acute liver toxicity of monocrotaline and to characterize the influence of its metabolism on its relative toxic potency compared to lasiocarpine and riddelliine. In the absence of data on acute liver toxicity of monocrotaline upon oral exposure, the predicted dose-response curve for acute liver toxicity in rats and the resulting benchmark dose lower and upper confidence limits for 10% effect (BMDL 10 and BMDU 10) were compared to data obtained in studies with intraperitoneal or subcutaneous dosing regimens. This indicated the predicted BMDL 10 value to be in line with the no-observed-adverse-effect levels (NOAELs) derived from availabe in vivo studies. The predicted BMDL 10-BMDU 10 of 1.1-4.9 mg/kg bw/day also matched the oral dose range of 1-3 mg PA/kg bw/ day at which adverse effects in human are reported. A comparison to the oral toxicity of the related pyrrolizidine alkaloids (PAs) lasiocarpine and riddelliine revealed that, although in the rat hepatocytes monocrotaline was less toxic than lasiocarpine and riddelliine, due to its relatively inefficient clearance, its in vivo acute liver toxicity was predicted to be comparable. It is concluded that the combined in vitro-PBK modeling approach can provide insight in monocrotaline-induced acute liver toxicity in rats, thereby filling existing gaps in the database on PA toxicity. Furthermore, the results reveal that the kinetic and metabolic properties of PAs can vary substantially and should be taken into account when considering differences in relative potency between different PAs. Keywords Monocrotaline • Acute toxicity • Liver • PBK modeling • Reverse dosimetry Abbreviations AIC Akaike information criterion ALT Alanine aminotransferase BMD 10 Benchmark dose resulting in a 10% effect above background level BMDL 10 Lower confidence limit of the BMD 10 BMDU 10 Upper confidence limit of the BMD 10 EFSA European Food Safety Authority GI Gastrointestinal GSH Glutathione HPC Hepatic parencymal cells HVOD Hepatic veno-occlusive disease Ka Absorption rate for uptake from the GI tract compartment into the liver PAs Pyrrolizidine alkaloids PBK Physiologically based kinetic POD Point of departure NOAEL No observed adverse effect level LOAEL Lowest observed adverse effect level pRPF Provisional relative potency factors 3Rs Replacement, reduction and refinement Electronic supplementary material The online version of this article (

show abstract

Section: Discussionsupporting

confidence: 91%

Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach

2020

View full text Add to dashboard Cite

show abstract

“…Use of these species in Brazilian ethnomedicine is for very specific applications, including as abortifacients or vermifuges. Crotalaria species contain the pyrrolizidine alkaloid (PA) monocrotaline, which has been investigated as an anti-tumor agent ( Kusuma et al, 2014 ). In contrast, the 26 species of Copaifera in Brazil, known to be of mild effect, have 70 use reports for six species.…”

Section: Discussionmentioning

confidence: 99%

Which Plants Used in Ethnomedicine Are Characterized? Phylogenetic Patterns in Traditional Use Related to Research Effort

2018

View full text Add to dashboard Cite

Plants are important resources in healthcare and for producing pharmaceutical drugs. Pharmacological and phytochemical characterization contributes to both the safe use of herbal medicines and the identification of leads for drug development. However, there is no recent assessment of the proportion of plants used in ethnomedicine that are characterized in this way. Further, although it is increasingly apparent that plants used in ethnomedicine belong to preferred phylogenetic lineages, it is not known how this relates to the focusing of research effort. Here we identify species and lineages rich in ethnomedicinal use and develop methods to describe how well they are known pharmacologically and/or phytochemically. We find 50% of plant species of the family Leguminosae used in ethnomedicine in Brazil, a geographical area where plants are an important part of healthcare, have been the focus of either phytochemical screening or testing for biological activity. Plant species which have more use reports are studied significantly more often (p < 0.05). Considering the taxonomic distribution of use, 70% of genera that include species with ethnomedicinal use have been studied, compared to 19% of genera with no reported use. Using a novel phylogenetic framework, we show that lineages with significantly greater numbers of ethnomedicinal species are phylogenetically over-dispersed within the family, highlighting the diversity of species used. “Hotnode clades” contain 16% of species but 46% of ethnomedicinally-used species. The ethnomedicinal species in hotnode clades have more use reports per species (p < 0.05), suggesting they are more frequently used. They are also more likely to be characterized pharmacologically and/or phytochemically. Research focus has followed traditional use by these measures, at least for these Brazilian plants, yet ethnomedicinal species yielding candidate drugs, raising public health concerns and more intensively studied lie outside of the hotnode clades.

show abstract

“…Rats had access to food and water ad libitum . The rats were divided into the following three equal groups at random: Control group, where rats received no treatment; model group, where rats underwent a left pneumonectomy plus subcutaneous injection of 60 mg/kg monocrotaline (MCT; Sigma-Aldrich; Merck KGaA, Darmstadt, Germany), a natural ligand exhibiting dose-dependent cytotoxicity with potent antineoplastic activity (20), at 7 days following the procedure; PTX group, where rats underwent the same procedure as those in the model group plus administration of 2 mg/kg PTX (Chongqing Pharmaceutical Group Co., Ltd., Yuzhong, China) via the caudal vein (21) daily for 1 week at 3 weeks following injection of MCT (6). Tests were performed and samples were collected from rats in all groups at 1 week following treatment.…”

Section: Methodsmentioning

confidence: 99%

Effects of paclitaxel intervention on pulmonary vascular remodeling in rats with pulmonary hypertension

Zhao

Yang

et al. 2018

Exp Ther Med

View full text Add to dashboard Cite

The aim of the present study was to investigate the effects of paclitaxel (PTX), at a non-cytotoxic concentration, on pulmonary vascular remodeling (PVR) in rats with pulmonary hypertension (PAH), and to explore the mechanisms underlying the PTX-mediated reversal of PVR in PAH. A total of 36 rats were divided into control group (n=12), model group (n=12) receiving a subcutaneous injection of monocrotaline (60 mg/kg) in the back on day 7 following left pneumonectomy and PTX group (n=12) with PTX (2 mg/kg) injection via the caudal vein 3 weeks following establishing the model. The degree of PVR among all groups, as well as the expression levels of Ki67, p27Kip1 and cyclin B1, were compared. The mean pulmonary artery pressure, right ventricular hypertrophy index [right ventricle/(left ventricle + septum) ratio] and the thickness of the pulmonary arterial tunica media in the model group were 58.34±2.01 mmHg, 0.64±0.046 and 65.3±3.3%, respectively, which were significantly higher when compared with 23.30±1.14 mmHg, 0.32±0.028 and 16.2±1.3% in the control group, respectively (P<0.01). The mean pulmonary artery pressure, right ventricular hypertrophy index and thickness of the pulmonary arterial tunica media in the PTX group were 42.35±1.53 mmHg, 0.44±0.029 and 40.5±2.6%, respectively, which were significantly lower when compared with the model group (P<0.01). Compared with the control group, the expression levels of Ki67 and cyclin B1 in the model group were significantly increased (P<0.01), while p27Kip1 expression was significantly reduced (P<0.01). Following PTX intervention, the expression levels of Ki67 and cyclin B1 were significantly reduced when compared with the model group (P<0.01), while p27Kip1 expression was significantly increased (P<0.01). The results of the present study suggest that PTX, administered at a non-cytotoxic concentration, may reduce PAH in rats, and prevent the effects of PVR in PAH. These effects of PTX may be associated with increased expression of p27Kip1 and decreased expression of cyclin B1.

show abstract

Antineoplastic Activity of Monocrotaline Against Hepatocellular Carcinoma

Cited by 8 publications

References 54 publications

Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach

Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach

Which Plants Used in Ethnomedicine Are Characterized? Phylogenetic Patterns in Traditional Use Related to Research Effort

Effects of paclitaxel intervention on pulmonary vascular remodeling in rats with pulmonary hypertension

Contact Info

Product

Resources

About