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Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
In rhubarb, the main anticancer anthraquinones were emodin, aloe-emodin, rhein, and chrysophanol (Figure 5.7). Early studies conducted on emodin showed that it could prevent cell proliferation in breast, cervical, colon, and prostate cancers (Chang et al., 1999; Pecere et al., 2000; Ren et al., 2018). Also, emodin has little or no cytotoxic effect in normal cells, suggesting that normal cells are comparatively safe than cancer cells when it comes to emodin-induced cytotoxicity. Aloe-emodin could inhibit the cell growth in many malignant tumors like hepatoma (liver) (Cha et al., 2005), human lung carcinoma (Chan et al., 1993; Jeon et al., 2012) and leukemia (Yeh et al., 2003). Jeon et al. (2012) treated hepatoma (HUH-7) cells with a dose-dependent concentration of aloe-emodin. He concluded that aloe-emodin could decrease CAPN2 and UBE3A, two essential proteins, which reduces cell growth and speeds up apoptosis. Since the mechanistic routes of aloe-emodin is unknown in H640 (lung cancer) cells, Yeh et al. (2003) conducted a study to evaluate the cytotoxicity of aloe-emodin in H640 cells. When introduced, the initial observation was apoptosis due to the modification of cAMP-dependent protein kinase. Other important protein expressions that were modified were BCL-3, protein kinase C, caspase-3, and p38.
Calpain as a therapeutic target in cancer
Published in Expert Opinion on Therapeutic Targets, 2022
Ivan Shapovalov, Danielle Harper, Peter A. Greer
The conventional calpain isoforms, calpain-1 and −2 (previously known as µ-calpain and m-calpain) were the first to be discovered and are the most well studied due to their abundant ubiquitous expression. Both isoforms are intracellular heterodimers consisting of a common regulatory subunit, encoded by the CAPNS1 gene (also known as CAPN4), and an isoform-specific catalytic subunit encoded by the CAPN1 or CAPN2 genes, for calpain-1 and calpain-2, respectively [10,11]. Calpain-1 and −2 are also considered classical calpains due to their defining domain structures. The catalytic subunit consists of an N-terminal anchor helix, a potential regulator of calpain activation [12]; two protease core domains that constitute the active site (PC1 and PC2); the calpain-type beta-sandwich (CBSW) domain (previously known as a C2-like domain); and a Ca2+ binding C-terminal penta EF-hand PEF(L) domain, a mediator of dimerization and a distinguishing feature of the classical calpain isoforms. The regulatory subunit CAPNS1 consists of an unstructured glycine rich (GR) domain; and a PEF(S) domain, which is homologous to the PEF(L) domain. A crystal structure of calpain-2 and domain maps for the catalytic (CAPN1/2) and regulatory (CAPNS1) subunits are shown in Figure 1.
Regulation of cytochrome P450 enzyme activity and expression by nitric oxide in the context of inflammatory disease
Published in Drug Metabolism Reviews, 2020
Edward T. Morgan, Cene Skubic, Choon-myung Lee, Kaja Blagotinšek Cokan, Damjana Rozman
Calpains are cysteine proteases, consisting of 15 members of which the best-characterized are Capn1 and Capn2 (Ono et al. 2016). These are also known as μ and m calpains, respectively activated by micromolar and millimolar concentrations of Ca++ (Liu et al. 2004; Ono et al. 2016). Calpains are found in almost every subcellular compartment including the ER and Golgi (Franco and Huttenlocher 2005). Although calpains can cleave many proteins, their roles in physiology are still not fully appreciated (Liu et al. 2004; Ono et al. 2016). Calpains are so-called ‘accessory’ or ‘modulator’ proteases that perform limited proteolysis by cleaving at distinct sites on a protein.
An update on the therapeutic potential of calpain inhibitors: a patent review
Published in Expert Opinion on Therapeutic Patents, 2020
About 45% of deaths in industrialized countries are due to fibrotic disease but there are only few treatments for this condition. The available treatments for fibrotic diseases such as idiopathic lung fibrosis, renal fibrosis, systemic sclerosis, and liver cirrhosis only alleviate some of the symptoms of the disease but do not treat the underlying pathophysiological cause. In their search for new agents to treat this condition, Kim and Dietz [71] disclosed that either broad-spectrum calpain inhibitors (e.g., MDL-28,170, SJA-6017, and calpeptin) or specific siRNA-mediated silencing of CAPN9 or CAPNS2 blocked TGF3-mediated myofibroblast differentiation (such as, epithelial- or endothelial-to-mesenchymal transition (EpMT or EnMT, respectively) and fibroblast-to-myofibroblast transition (FMT)) so they claimed that CAPN9 and/or CAPNS2 inhibitors are potential treatments for diseases associated with myofibroblast differentiation. This was followed by disclosures from Blade Therapeutics, Inc [7273–74] in which several macrocyclic (general structures 44 and 45) and non-macrocyclic (general structure 46) calpain inhibitors were synthesized and studied as treatments for fibrotic disease (Figure 12). Unlike the report by Kim and Dietz, the Blade compounds were investigated as inhibitors of CAPNl, CAPN2, and/or CAPN9 and were found to inhibit these calpain isoforms with IC50 values between < 3 uM and > 25 uM. The compounds were claimed to be broadly effective in treating a host of conditions arising from fibrosis or inflammation, specifically those associated with myofibroblast differentiation. The compounds are not particularly effective calpain inhibitors hence potent and selective inhibitors that target these calpain isoforms are needed to establish them that as viable drug targets for fibrotic disease.