The role of usnic acid-induced apoptosis and autophagy in hepatocellular carcinoma

Abstract

<jats:p> Usnic acid (UA) is a multifunctional bioactive lichen secondary metabolite with potential anti-cancer properties. Although the promising therapeutic effects of UA have been investigated in different cancer cell lines, the mechanism driving UA-induced cell death has yet to be elucidated. As the type of cell death (apoptosis or autophagy) induced by UA may vary depending on the cancer cell type, we first studied the cytotoxic effects of UA in HEPG2 (HBV(−)) and SNU-449(HBV(+)) hepatocellular carcinoma (HCC) cell lines. HCC cell viability was considerably reduced in a dose-dependent manner at 12, 24, and 48 h after treatment with UA ( p &lt; 0.05). However, SNU-449 cells were more sensitive to UA than HEPG2 cells. UA also induced apoptotic cell death in HCC cells with cell cycle arrest at G0/G1 and G2/M phase depending on the genetic profile of each cell type. On the other hand, we observed acidic vesicular organelles in HCC cells after 36 h of UA treatment. Taken together, these findings suggest that UA stimulates apoptosis and autophagy in HEPG2 and SNU-449 cells without damaging normal control cells. Thus, UA might be a potential therapeutic compound for HCC treatment. However, there is a need for further studies investigating the death-promoting or preventing roles for autophagy and the molecular signaling mechanisms induced by UA treatment. </jats:p>

Investigation of new treatment option for hepatocellular carcinoma: a combination of sorafenib with usnic acid

“…As a lichen secondary metabolite, usnic acid (UA) has become the most extensively studied substance for cancer therapy due to its unique properties. The results including our previous one indicate that UA has antitumour activity in a variety of cancer cell types by inhibiting the proliferation of cancer cells dose‐ and time‐dependently and inducing apoptosis and autophagy, in vitro and in vivo …”

“…Natural products isolated from plants have provided a rich source of therapeutic agents for the treatment of cancer due to low toxicity . It is well known that natural product‐derived anticancer drugs have clinically used or in clinical trials as anticancer agents.…”

Anticancer Potential of Lichens’ Secondary Metabolites

“…The cytotoxic activity of lichens was observed in different cancer cell lines and we have noticed that the cytotoxic abilities of lichens in cancer cells are higher than in non-cancer cells [21,23]. First of all, the strong cytotoxic capacity of lichens against cancer cells is mediated through the processes including apoptosis, necrosis or autophagy together with the cell cycle arrest at G2/M, S, or G0/G1 phases [27]. Lichens act also as regulators of the cell cycle through the various mechanisms, such as those associated with cyclin-dependent kinases (CDK4, CDK6) or cyclin D1 [28].…”

“…In regard to programmed cell death, lichens act as activators of apoptosis in various cancer cells [21,26] through the modulation of gene expression of products related to apoptosis such as caspases, p53, p38, or anti-/pro-apoptotic proteins of Bcl-2 family [29]. Induction of apoptosis by lichens might be associated also with an increase of cleaved PARP, a stress response protein repairing damaged DNA and regulating chromatin structure [30], with inactivation of the mammalian target of rapamycin (mTOR) or activation of c-Jun N-terminal kinase (JNK) signaling [27]. Anti-proliferative effects of lichens can be modulated through the regulation of other signaling pathways such as ERK1/2 and AKT [31] or proliferation protein marker Ki-67 [32].…”

“…Indeed, enrichment analysis revealed different groups of miRNA with targets as follows: Apoptosis, Hedgehog, TGF-β, and MAPK pathways identified as prominent [37]. Pro-apoptotic abilities of UA were demonstrated through the G0/G1 and G2/M cell cycle arrest in both hepatocellular carcinoma HepG2 and SNU-449 cells [27]. Similarly, an application of UA in lung cancer cells (A549) led to the decrease of cells, induced apoptosis and inhibited cell proliferation, which was accompanied by G0/G1 cell cycle arrest, decreased expression of CDK4, CDK6, and cyclin D1 and increased expression of CDK inhibitor (CDKI) p21/cip1 protein.…”