Experimental evidence for use of Acorus calamus (asarone) for cancer chemoprevention

Abstract

Cancer is one of the major non-communicable diseases posing substantial challenges in both developing and developed countries. The options available for treatment of different cancer are associated with various limitations, including severe toxicity, drug resistance, poor outcomes and a high risk of relapse. Hence, an increased attention and necessity for screening of various phytochemicals from natural sources for superior and safer alternative has been ongoing for several decades. In recent years, phytochemicals like galantamine, erwinaze, rivastigmine, resveratrol from natural sources have been found to be important therapeutic targets for the treatment of various diseases including cancer, neurodegeneration, diabetes, and cardiovascular effects. Acorus calamus (Sweet flag), and/or its bioactive phytochemical alpha (α)-and beta (β)-asarone, is a well-known drug in the traditional system of medicine which possesses anti-tumor and chemo-preventive activities as evident from numerous pre-clinical studies both in-vitro and in-vivo. In this article, we critically review the current available scientific evidences of A. calamus and/or asarone for cancer chemoprevention based on preclinical in-vitro and in-vivo models. In addition, we also have compiled and discussed the molecular targets of mechanism(s) involved in the anti-cancer activity of A. calamus/asarone. Still, extensive in-vivo studies are necessary using various animal models to understand the molecular mechanism behind the pharmacological activity of the bioactive phytochemicals derived from A. calamus. It is strongly believed that the comprehensive evidence presented in this article could deliver a possible source for researchers to conduct future studies pertaining to A. calamus and/or its bioactive phytochemicals asarone for cancer chemoprevention.

Keywords: Biochemistry; Cancer research; Cell biology; Evidence-based medicine; Molecular biology; Oncology.

Fig. 1

Chemical structures of various constituents obtained from A. calamus.

Fig. 2

Schematic representation of various pharmacological activity of A. calamus and/or its bioactive phytochemicals asarone (alpha (α)-and, beta (β)-asarone).

Fig. 3

Number of publications per year on A. calamus and/or its bioactive phytochemicals asarones. The PubMed database (https://www.ncbi.nlm.nih.gov/pubmed/) was searched with the keywords “Acorus calamus and cancer” and “asarone and cancer”.

Fig. 4

The possible site of action of beta (β) asarone in apoptosis, cell proliferation and growth. (A) The (β)-asarone regulates the levels of the key proteins involved in the cell death and mitochondrial apoptosis pathway. (β)-asarone results in enhancement of the ratio of Bcl-xS/Bcl-xL via inhibition of hnRNP A2/B1-mediated signaling pathway, which may be correlated with (β)-asarone-induced apoptosis. On the other hand, the increased expression of cleaved-caspase 3, 8 and 9 along with the activation of the death receptor proteins TNF-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL), it results in the induction of apoptosis. (B) (β)-asarone induced the cell cycle arrest at G₀/G₁ phase through the up-regulation of cell cycle related proteins as p21 and p27 and down-regulation of cyclin D, cyclin E, Cdc25A and CDK2. [Possible site of action of (β)-asarone as observed in glioblastoma (U251 cells), colon cancer (LoVo cells), colorectal cancer (HT29 and SW480 cells), gastric cancer (SGC-7901, BGC-823 and MKN-28 cells), gastric adenocarcinoma (AGS cells), fibroblast (HSkMC cells) and prostate cancer (LNCaP cells)].

Fig. 5

The possible site of action of A. calamus and/or its bioactive phytochemicals asarone (alpha (α)-and, beta (β)-asarone) in tumor cell metastasis, invasion, migration and angiogenesis. (A) The (β)-asarone decreases the expression of epithelial-mesenchymal transition (EMT) through upregulation of E-cadherin and down-regulation of vimentin or N-cadherin via inhibition of the expression of hnRNP A2/B1-mediated signaling pathway, thereby suggesting (β)-asarone may block the process of EMT process in cancerous cells. (B) Matrix metalloproteinases (MMPs) are involved in the hnRNP A2/B1-related cancer invasion, migration and metastasis. A. calamus and/or asarone suppresses the expression of matrix metalloproteinases (MMP-2, 9 and 14) and vascular endothelial growth factor (VEGF) thereby underlying the inhibitory effect on invasion, migration and metastasis. [Possible site of action of A. calamus and/or its bioactive phytochemicals asarone (alpha (α)-and, beta (β)-asarone) as observed in glioblastoma (U251 cells), colon cancer (LoVo cells), gastric cancer (SGC-7901, BGC-823 and MKN-28 cells) and prostate cancer (LNCaP cells)].

Fig. 6

The possible site of action of A. calamus and/or its bioactive phytochemicals asarone (alpha (α)-and, beta (β)-asarone) in cellular senescence and autophagy. It inhibits carcinogenesis by inducing cellular senescence through activation of lamin B1. Elevated lamin B1 promotes p53 and p21 expression, and recruits Oct-1 or 4 onto nuclear envelope and prevents binding to the p15 promoter, upregulating p15. On the other hand, activated p53 inhibits Bcl-2, which induces cell apoptosis in the cell cycle. Further autophagy is promoted through up-regulation of autophagy related proteins (Beclin-1 and LC3-II/I) and down-regulation of p53 related proteins (mTOR, Bcl-2). Atg: Autophagy related gene; mTOR: Mammalian target of rapamycin; Oct-1/4: Octamer-binding protein-1,4; LC3: Microtubule-associated proteins 1A/1B light chain 3B. [Possible site of action of A. calamus and/or its bioactive phytochemicals asarone (alpha (α)-and, beta (β)-asarone) as observed in glioblastoma (U251 cells), colorectal cancer (HT29 and SW480 cells), fibroblast (HSkMC cells) and gastric adenocarcinoma (AGS cells)].