Hederagenin Induces Apoptosis in Cisplatin‐Resistant Head and Neck Cancer Cells by Inhibiting the Nrf2‐ARE Antioxidant Pathway

Abstract

Acquired resistance to cisplatin is the most common reason for the failure of cisplatin chemotherapy. Hederagenin, triterpenoids extracted from ivy leaves, exhibits antitumor activity in various types of cancer. However, the therapeutic potential of hederagenin in head and neck cancer (HNC) has remained unclear. Therefore, we examined the effects of hederagenin in cisplatin-resistant HNC cells and characterized its molecular mechanisms of action in this context. We evaluated the effects of hederagenin treatment on cell viability, apoptosis, reactive oxygen species (ROS) production, glutathione levels, mitochondrial membrane potential (ΔΨm), and protein and mRNA expression in HNC cells. The antitumor effect of hederagenin in mouse tumor xenograft models was also analyzed. Hederagenin selectively induced cell death in both cisplatin-sensitive and cisplatin-resistant HNC cells by promoting changes in ΔΨm and inducing apoptosis. Hederagenin inhibited the Nrf2-antioxidant response element (ARE) pathway and activated p53 in HNC cells, thereby enhancing ROS production and promoting glutathione depletion. These effects were reversed by the antioxidant trolox. Hederagenin activated intrinsic apoptotic pathways via cleaved PARP, cleaved caspase-3, and Bax. The selective inhibitory effects of hederagenin were confirmed in cisplatin-resistant HNC xenograft models. These data suggest that hederagenin induces cell death in resistant HNC cells via the Nrf2-ARE antioxidant pathway.

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Despite the increasing demand for negative modulators of NRF2, selective inhibitors are neither currently available nor under clinical trial evaluation. Yet, alternative strategies have been explored based on the pharmacologic manipulation of various NRF2 modulators through natural and synthetic compounds [302,303]. Historically, many natural compounds have been used to treat human pathologies, including cancer.…”

Current knowledge and development of hederagenin as a promising medicinal agent: a comprehensive review

“…HG has been shown to have a wide range of potential anti-tumor effects both in vitro and in vivo, which have been evaluated in various types of cancers, including lung, colon, stomach, liver, ovarian, prostate, breast, and endometrial cancers. 2,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Table 4 summarizes the anti-tumor activity of HG in different tumor cell lines and animal models. Considerable attention has been devoted to the anti-tumor effect of HG in many tumor cell lines.…”

“…The mechanism was related to activating intrinsic apoptotic pathways via cleaved poly ADP-ribose polymerase, cleaved caspase-3, and Bax. 14 In addition, investigation of the anti-colon cancer effect of HG has attracted special attention. In a study by Y. Chen, 5 HG suppressed epithelial-mesenchymal transition and invasion of the colon cancer cells SW480 in a dose-and time-dependent manner.…”

“…4 In recent years, HG has been observed to be biologically active, as well as many other saponins with similar structures, such as ursolic acid and corosolic acid. HG exhibits multiple pharmaceutical and biological activities, including antitumor, 2,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] anti-inammatory, [24][25][26][27][28][29][30] anti-depressant, [31][32][33][34][35] antineurodegenerative, [36][37][38] anti-hyperlipidemia, 4,39,40 anti-diabetic, [41][42][43] anti-leishmanial, 19,44,45 and anti-viral (against hepatitis B) activity. 46 Recently, a number of studies have investigated the use of HG as a potential anti-tumor agent.…”

“…46 Recently, a number of studies have investigated the use of HG as a potential anti-tumor agent. 5,6,[10][11][12][14][15][16] The pharmacokinetics, [47][48][49][50][51] structural modication, [17][18][19][20][21]35,38,45,46 and mechanisms of action [4][5][6][10][11][12][13][14][15][16]19,25,26,[31][32][33][34]36,37,39,40,43,45 of HG have also been studied. However, possibly owing to limited in vivo data, HG is still in the preclinical development stage.…”