Studies of the chronic toxicity of tetrandrine in dogs: An inhibitor of silicosis

doi:10.1016/0147-6513(82)90034-3

Ecotoxicology and Environmental Safety

Volume 6, Issue 6, December 1982, Pages 528-534

https://doi.org/10.1016/0147-6513(82)90034-3 Get rights and content

Abstract

Dogs administered tetrandrine at low dose (3 mg/kg) and medium dose (10 mg/kg) levels showed no toxic changes. Administration of the drug at a high dose level (40 mg/kg) for 2 months may induce focal necrosis of liver cells, abnormal liver function, and acceleration of erythrocyte sedimentation rate. After the dogs had received tetrandrine for 6 months continuously, necrosis of liver tissue appeared. After continuous administration of tetrandrine, accumulation of the drug in liver, lung, kidney, and adrenal gland was observed. The amount of drug stored in the organs increased with the quantity of drug given to the animal.

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Although tetrandrine (1) also considerably inhibited proliferation of RIL175 cells (IC50 9.1 μM), antiproliferative effects were markedly enhanced for SG-005 (2) and SG-094 (3) (IC50 2.4 and 3.7 μM, respectively). Tetrandrine (1) has serious deficiencies, which include its structural complexity and its toxicity (Jin et al., 2011; Li et al., 2019a; Qi et al., 2013; Tainlin et al., 1982; Yan et al., 2006). To cope with these limitations, we synthesized and characterized various analogs of the lead molecule.
The role of two-pore channel 2 (TPC2), one of the few cation channels localized on endolysosomal membranes, in cancer remains poorly understood. Here, we report that TPC2 knockout reduces proliferation of cancer cells in vitro, affects their energy metabolism, and successfully abrogates tumor growth in vivo. Concurrently, we have developed simplified analogs of the alkaloid tetrandrine as potent TPC2 inhibitors by screening a library of synthesized benzyltetrahydroisoquinoline derivatives. Removal of dispensable substructures of the lead molecule tetrandrine increases antiproliferative properties against cancer cells and impairs proangiogenic signaling of endothelial cells to a greater extent than tetrandrine. Simultaneously, toxic effects on non-cancerous cells are reduced, allowing in vivo administration and revealing a TPC2 inhibitor with antitumor efficacy in mice. Hence, our study unveils TPC2 as valid target for cancer therapy and provides easily accessible tetrandrine analogs as a promising option for effective pharmacological interference.
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Botany, traditional uses, phytochemistry, pharmacokinetic and toxicity of 13 alkaloids, namely, tetrandrine, dauricine, curine, trilobine, isotrilobine, cepharanthine, daurisoline, thalicarpine, thalidasine, isotetrandrine, liensinine, neferine and isoliensinine, have been summarized in this paper. It can't be denied that these alkaloids are important material basis of pharmacological effects of family Menispermaceae and others, and for traditional and local uses which has been basically reproduced in the current studies. The 13 BBIQ alkaloids in this paper showed strong affinity and inhibitory effect on P-glycoprotein (P-gp), with poor oral absorption and potent binding ability with plasma protein. BBIQ alkaloids represented by tetrandrine play a key role in regulating P-gp or reversing multidrug resistance (MDR) in a variety of tumors. The irrationality of their usage could pose a risk of poisoning in vivo, including renal and liver toxicity, which are related to the formation of quinone methide during metabolism.
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The plant bisbenzylisoquinoline alkaloid tetrandrine (1) has diverse pharmacological properties [3,4], including antiviral [5–8], anticancer [9,10], multidrug resistance reversing [11–15] and calcium channel blocking [6,16–18] activities, making this alkaloid an attractive drug candidate. Unfortunately, its clinical application is limited by its toxicity, mainly affecting liver and lungs [26–30]. Five diastereomeric pairs of novel analogues of tetrandrine and its natural diastereomer isotetrandrine, respectively, were synthesized and biologically evaluated with respect to their toxicity, their antiproliferative and multidrug resistance reversing activity.
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Studies of the chronic toxicity of tetrandrine in dogs: An inhibitor of silicosis

Abstract

J. Biol. Chem.

Biochem. Pharmacol.