Identification of Arctigenin as an Antitumor Agent Having the Ability to Eliminate the Tolerance of Cancer Cells to Nutrient Starvation

Abstract

Tumor cells generally proliferate rapidly and the demand for essential nutrients as well as oxygen always exceeds the supply due to the unregulated growth and the insufficient and inappropriate vascular supply. However, cancer cells show an inherent ability to tolerate extreme conditions, such as that characterized by low nutrient and oxygen supply, by modulating their energy metabolism. Thus, targeting nutrientdeprived cancer cells may be a novel strategy in anticancer drug development. Based on that, we established a novel screening method to discover anticancer agents that preferentially inhibit cancer cell viability under the nutrientdeprived condition. After screening 500 medicinal plant extracts used in Japanese Kampo medicine, we found that a CH 2 Cl 2 -soluble extract of Arctium lappa exhibited 100% preferential cytotoxicity under the nutrient-deprived condition at a concentration of 50 Mg/mL with virtually no cytotoxicity under nutrient-rich condition. Further bioassayguided fractionation and isolation led to the isolation of arctigenin as the primary compound responsible for such preferential cytotoxicity; the compound exhibited 100% preferential cytotoxicity against nutrient-deprived cells at a concentration of 0.01 Mg/mL. Furthermore, arctigenin was also found to strongly suppress the PANC-1 tumor growth in nude mice, as well as the growth of several of the tested pancreatic cancer cell lines, suggesting the feasibility of this novel antiausterity approach in cancer therapy. Further investigation of the mechanism of action of arctigenin revealed that the compound blocked the activation of Akt induced by glucose starvation, which is a key process in the tolerance exhibited by cancer cells to glucose starvation.

A review of the pharmacological effects of Arctium lappa (burdock)

“…Arctigenin, an active compound found in the seeds of burdock, has the ability to eradicate nutrient-deprived cancer cells (Awale et al, 2006). In addition to its board spectrum of activities on different cancer cell lines, e.g.…”

Estonian folk traditional experiences on natural anticancer remedies: From past to the future

“…In contrast, roots of Arctium lappa L. (Asteraceae) (burdock) have hepatoprotective activities (Chan et al, 2011;Predes et al, 2011) and extract of this herb has shown antiproliferative effects on various cancer cells (Predes et al, 2011;Wegiera et al, 2012). Purification of active compound from the seed extract of Arctium lappa has led to the identification of lignan arctigenin as tumor-specific agent showing cytotoxicity to gastric, liver, colon, starved pancreas, and lung cancer as well as leukemia cells (Awale et al, 2006;Chan et al, 2011;Matsumoto et al, 2006;Predes et al, 2011;Susanti et al, 2012). A remarkable antineoplastic activity has demonstrated also for the extract prepared from Inula helenium L. (Asteraceae) roots revealing toxicity toward different tumor cell lines, including gastric, colon, liver, pancreas, mammary, and cervical cancer as well as astrocytoma, leukemia and melanoma cells (Dorn et al, 2006).…”

Arctigenin alleviates ER stress via activating AMPK

“…The root of Arctium lappa L, a popular edible vegetable in China and Japan, is used to make a general health tonic. Previous studies have shown that ATG exerted protective effects against oxidation [12] , viral infection [13] , and cancer [14] . Most recently, two research groups have reported that ATG could block the UPR and preferentially inhibit tumor cell viability under glucose-deprived conditions [15,16] .…”