Pharmacogenomics of Scopoletin in Tumor Cells

Abstract

Drug resistance and the severe side effects of chemotherapy necessitate the development of novel anticancer drugs. Natural products are a valuable source for drug development. Scopoletin is a coumarin compound, which can be found in several Artemisia species and other plant genera. Microarray-based RNA expression profiling of the NCI cell line panel showed that cellular response of scopoletin did not correlate to the expression of ATP-binding cassette (ABC) transporters as classical drug resistance mechanisms (ABCB1, ABCB5, ABCC1, ABCG2). This was also true for the expression of the oncogene EGFR and the mutational status of the tumor suppressor gene, TP53. However, mutations in the RAS oncogenes and the slow proliferative activity in terms of cell doubling times significantly correlated with scopoletin resistance. COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression resulted in a set of 40 genes, which all harbored binding motifs in their promoter sequences for the transcription factor, NF-κB, which is known to be associated with drug resistance. RAS mutations, slow proliferative activity, and NF-κB may hamper its effectiveness. By in silico molecular docking studies, we found that scopoletin bound to NF-κB and its regulator IκB. Scopoletin activated NF-κB in a SEAP-driven NF-κB reporter cell line, indicating that NF-κB might be a resistance factor for scopoletin. In conclusion, scopoletin might serve as lead compound for drug development because of its favorable activity against tumor cells with ABC-transporter expression, although NF-κB activation may be considered as resistance factor for this compound. Further investigations are warranted to explore the full therapeutic potential of this natural product.

Optimisation of artemisinin and scopoletin extraction from Artemisia annua with a new modern pressurised cyclic solid–liquid (PCSL) extraction technique

“…Scopoletin (6‐methoxy‐7‐hydroxycomarin) is a phenolic coumarin and an important member of the group of phytoalexins isolated from many plants . A variety of biological activities like anti‐inflammatory, anti‐allergy and anti‐angiogenesis have been reported for scopoletin, known also for its cytotoxicity towards cancer cells …”

“…43 A variety of biological activities like antiinflammatory, anti-allergy and anti-angiogenesis have been reported for scopoletin, known also for its cytotoxicity towards cancer cells. [19][20][21] In the literature, there are many different extraction techniques used to obtain artemisinin in particular from the fresh plant matrix. The methods used are generally time-consuming, needing often instruments with relatively critical purchase and operating costs, and also showing a strong environmental impact and extractive efficiency that is not always optimal ( Table 2).…”

“…A variety of other biological activities like anti‐inflammatory, anti‐allergy and anti‐angiogenesis have been ascribed to scopoletin (Figure ), a phenolic coumarin and an important phytoalexin isolated from many plants . Scopoletin is also known for its cytotoxicity towards cancer cells …”

“…17,18 Scopoletin is also known for its cytotoxicity towards cancer cells. [19][20][21] Despite numerous attempts to synthesise artemisinin in vitro, to date the only pharmacological source of this molecule remains the plant. The main commercial extraction process is based on the use of hot petroleum ether as extracting agent, sometimes modified with ethyl acetate (EtOAc) to increase solubility of artemisinin.…”

Molecules and functions of aesculus chinensis bunge bark volatiles

“…In addition, studies have reported that Moxa Coccinea has analgesic, anti-inflammatory and antioxidant effects (Jamuna et al, 2015), blood pressure lowering and antispasmodic effects, especially antitumor (Liu et al, 2012;Tabana et. al., 2016;Seo et al, 2016;Zhao et al, 2012) and its activity in the prevention and treatment of hyperuricemia (Yao et al, 2012), has currently attracted widespread attention at home and abroad. It can prevent alcohol-induced Hepatic lipid accumulation (Lee et al, 2014), insecticidal activity, acaricidal activity, antibacterial activity, growth regulation, and induction of plant resistance (Hino, Okazaki and Miura, 2014).…”