OCT1 (IC50 = 36.8 μM); OCT2 (IC50 = 1852.6 μM)

Monocrotaline is a naturally occurring ligand that has strong anti-tumor action and dose-dependent cytotoxicity. Monocrotaline has been shown to have an IC50 of 24.966 µg/mL and a genotoxicity of 2 times IC50 in vitro when tested on HepG2 cells [2].

A rat model of hypertension can be created via animal modeling with monocrotaline. In rats, MCT results in pulmonary vascular syndrome, which is typified by cor pulmonale, pulmonary hypertension (PH), and proliferative pulmonary vasculitis [3]. Monocrotaline-induced animal models have the advantage of closely resembling several important aspects of human pulmonary arterial hypertension (PAH) in preclinical models, such as vascular remodeling, smooth muscle cell proliferation, endothelial dysfunction, inflammatory cytokine upregulation, and right ventricular failure. [4]. The administration of monocrotaline resulted in alterations to several pathways linked to the pathogenesis of peripheral hemorrhage (PH), such as the stimulation of glycolysis, elevations in markers of proliferation, disturbance of carnitine homeostasis, elevations in biomarkers of inflammation and fibrosis, and glutathione production. decrease[5]. Rats given a single dosage of monocrotaline (60 mg/kg i.p.) have considerably higher pulmonary artery pressure, as well as increased right ventricular hypertrophy and pulmonary artery structural remodeling. Then, astragaloside IV (ASIV) was given for 21 days at doses of 10 and 30 mg/kg/d. By enhancing pulmonary arterial remodeling and inflammation, ASIV can prevent pulmonary hypertension [7]. A rat model of pulmonary arterial hypertension (PAH) is induced by monocrotaline (60 mg/kg; ip; single dose) after 3–4 weeks [7]. In a rat model of left lung resection, monocrotaline (60 mg/kg; i.p.; single dose) exhibited significant antitumor efficacy along with dose-dependent cytotoxicity [9]. 1 N HCl was used to dissolve the monocrotaline, which was then diluted with sterile saline and brought to pH 7.4 using 1 N NaOH [7].

Current study systematically investigated the interaction of two alkaloids, anisodine and monocrotaline, with organic cation transporter OCT1, 2, 3, MATE1 and MATE2-K by using in vitro stably transfected HEK293 cells. Both anisodine and monocrotaline inhibited the OCTs and MATE transporters. The lowest IC50 was 12.9 µmol·L-1 of anisodine on OCT1 and the highest was 1.8 mmol·L-1 of monocrotaline on OCT2. Anisodine was a substrate of OCT2 (Km = 13.3 ± 2.6 µmol·L-1 and Vmax = 286.8 ± 53.6 pmol/mg protein/min). Monocrotaline was determined to be a substrate of both OCT1 (Km = 109.1 ± 17.8 µmol·L-1, Vmax = 576.5 ± 87.5 pmol/mg protein/min) and OCT2 (Km = 64.7 ± 14.8 µmol·L-1, Vmax = 180.7 ± 22.0 pmol/mg protein/min), other than OCT3 and MATE transporters. The results indicated that OCT2 may be important for renal elimination of anisodine and OCT1 was responsible for monocrotaline uptake into liver. However neither MATE1 nor MATE2-K could facilitate transcellular transport of anisodine and monocrotaline. Accumulation of these drugs in the organs with high OCT1 expression (liver) and OCT2 expression (kidney) may be expected[8].

Cell Viability Assay[2]
Cell Types: HepG2 cells
Tested Concentrations: 25, 50, 100 and 200 µg/mL
Incubation Duration: 48 h
Experimental Results: Induced apoptosis rate was dose-dependent.

Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling[7]
Male Sprague-Dawley rats, 8 weeks old weighing 200-230 g, were obtained from the Animal Center of Qiqihar Medical University. The protocol for the present study was approved by the Qiqihar Medical University Institutional Review Board (no. QMU-AECC-2018-27). The rats were housed in a temperature- and humidity-controlled environment with 12-h light/dark cycles. Food and water were available ad libitum. The experiments conformed to the National Institutes of Health guidelines concerning the care and use of laboratory animals, and all animal procedures were approved by the Animal Care and Use Committee of the Qiqihar Medical University. The rats were randomly assigned to 4 groups (8 rats per group) as follows: The control group, the monocrotaline (MCT) group, the MCT + 10 mg/kg/dahy ASIV (ASIV10) group, and the MCT + 30 mg/kg/day ASIV (ASIV30) group. To establish MCT-induced PAH, the rats were administered a single intraperitoneal injection of MCT (60 mg/kg), while the control group received the same volume of saline. MCT was dissolved in 1 N HCl, diluted in sterile saline and adjusted to pH 7.4 with 1 N NaOH. ASIV was initially dissolved in DMSO as a stock solution and further diluted in saline immediately prior to use; the final DMSO concentration was 0.5%. Within hours of the MCT injection, there were signs of pulmonary vascular endothelial damage, but without an increase in pulmonary artery pressure. By 2 weeks, pulmonary artery pressure began to increase, as previously described. At 2 days following the MCT administration, ASIV or the vehicle (0.5% DMSO in saline) were administered intraperitoneally once a day for 21 days.

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A total of 36 male specific-pathogen free Sprague-Dawley rats (age, 6–8 weeks; weight, 300–350 g) were kept in a conventional room at 22±2°C, a relative humidity of 55±10% and a 12-h light/dark cycle. 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), a natural ligand exhibiting dose-dependent cytotoxicity with potent antineoplastic activity, 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 via the caudal vein (21) daily for 1 week at 3 weeks following injection of MCT[9].

[1]. Gomez-Arroyo JG, et al. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol. 2012 Feb 15;302(4):L363-9.
[2]. Kusuma SS, et al. Antineoplastic activity of monocrotaline against hepatocellular carcinoma. Anticancer Agents Med Chem. 2014;14(9):1237-48.
[3]. Wilson DW, et, al. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol. 1992;22(5-6):307-25.
[4]. Nogueira-Ferreira R, et al. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach. Pulm Pharmacol Ther. 2015 Dec;35:8-16.
[5]. Rafikova O,et al. Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed RatLung. PLoS One. 2016 Mar 3;11(3):e0150480.
[6]. Wu XH, et al. Experimental animal models of pulmonary hypertension: Development and challenges. Animal Model Exp Med. 2022 Sep; 5(3):207-216.
[7]. Jin H, et al. Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling. Int J Mol Med. 2021 Feb;47(2):595-606.
[8]. Chen JY, et al. An in vitro study on interaction of anisodine and monocrotaline with organic cation transporters of the SLC22 and SLC47 families. Chin J Nat Med. 2019 Jul;17(7):490-497.
[9]. Zhao J, et al. Effects of paclitaxel intervention on pulmonary vascular remodeling in rats with pulmonary hypertension. Exp Ther Med. 2019 Feb;17(2):1163-1170.

C16H23NO6

325.36

325.15252

C, 59.07; H, 7.13; N, 4.31; O, 29.50

315-22-0

Typically exists as white to off-white solids at room temperature

1.4±0.1 g/cm3

537.3±50.0 °C at 760 mmHg

204ºC

278.7±30.1 °C

0.0±3.2 mmHg at 25°C

1.586

-0.37

96.3

O=C(O[C@]1([H])CCN2[C@]1([H])C(CO3)=CC2)[C@H](C)[C@@](C)(O)[C@@](C)(O)C3=O

QVCMHGGNRFRMAD-XFGHUUIASA-N

InChI=1S/C16H23NO6/c1-9-13(18)23-11-5-7-17-6-4-10(12(11)17)8-22-14(19)16(3,21)15(9,2)20/h4,9,11-12,20-21H,5-8H2,1-3H3/t9-,11+,12+,15+,16-/m0/s1

20-Norcrotalanan-11,15-dione, 14,19-dihydro-12,13-dihydroxy-, (13-alpha,14-alpha)- (9CI)

NSC 28693; NSC-28693; NSC28693

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

1M HCl : 200 mg/mL (~614.70 mM)
DMSO : ~25 mg/mL (~76.84 mM)
H2O : ~2 mg/mL (~6.15 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.68 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.68 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.39 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 4: ≥ 2.08 mg/mL (6.39 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.08 mg/mL (6.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 6: ≥ 0.5 mg/mL (1.54 mM)(saturation unknown) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.

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Solubility in Formulation 7: 4.17 mg/mL (12.82 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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Solubility in Formulation 8: 21 mg/mL (64.54 mM) in 20% HP-β-CD in Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; Need ultrasonic and warming and heat to 53°C.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)