Therapeutic Emergence of Rhein as a Potential Anticancer Drug: A Review of Its Molecular Targets and Anticancer Properties

Abstract

According to the World Health Organization (WHO), cancer is the second-highest cause of mortality in the world, and it kills nearly 9.6 million people annually. Besides the fatality of the disease, poor prognosis, cost of conventional therapies, and associated side-effects add more burden to patients, post-diagnosis. Therefore, the search for alternatives for the treatment of cancer that are safe, multi-targeted, effective, and cost-effective has compelled us to go back to ancient systems of medicine. Natural herbs and plant formulations are laden with a variety of phytochemicals. One such compound is rhein, which is an anthraquinone derived from the roots of Rheum spp. and Polygonum multiflorum. In ethnomedicine, these plants are used for the treatment of inflammation, osteoarthritis, diabetes, and bacterial and helminthic infections. Increasing evidence suggests that this compound can suppress breast cancer, cervical cancer, colon cancer, lung cancer, ovarian cancer, etc. in both in vitro and in vivo settings. Recent studies have reported that this compound modulates different signaling cascades in cancer cells and can prevent angiogenesis and progression of different types of cancers. The present review highlights the cancer-preventing and therapeutic properties of rhein based on the available literature, which will help to extend further research to establish the chemoprotective and therapeutic roles of rhein compared to other conventional drugs. Future pharmacokinetic and toxicological studies could support this compound as an effective anticancer agent.

Keywords: cancer; chemoprevention; chemotherapy; molecular targets; phytochemical; rhein.

Figure 1

Sources of rhein: (A) Rheum rhabarbarum (Kay Yatskievych/ www.discoverlife.org); (B) Aloe spp. (Pankaj Oudhia/ www.discoverlife.org); (C) Cassia fistula (John Pickering/ www.discoverlife.org); (D) Polygonum cuspidatum (Les Mehrhoff/ www.discoverlife.org).

Figure 2

Anticancer activity of rhein in different cancers.

Figure 3

Molecular targets of rhein. Abbreviations: Ac-K100: acetylated lysine; Bax: Bcl-2-associated X protein; Bcl-2: B cell lymphoma 2; Bid: BH3 interacting domain death agonist; CDK: cyclin-dependent kinase; CHOP: CCAAT/enhancer-binding protein homologous protein; COX-2: cyclooxygenase 2; Cyt c: cytochrome c; EGF: extracellular growth factor; Fas: FS-7-associated surface antigen; GRP78: 78 kDa glucose regulated protein; HER-2: human epidermal growth factor receptor 2; HIF-1α: hypoxia-inducible factor 1 alpha; HK-2: hexokinase 2; HMGB1: high-mobility-group-box-1; IKKβ: inhibitor of nuclear factor kappa-B kinase subunit beta; IL: interleukin; iNOS: inducible nitric oxide synthase; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MDM2: murine double minute-2; MEK: mitogen-activated protein kinase kinase; MMP-9: Matrix metalloproteinase-9; NADPH: nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factor kappa light chain enhancer of activated B cells; PARP: poly ADP ribose polymerase; p-c-Jun: phosphorylated c-Jun; pERK: phosphorylated extracellular signal-regulated kinase; PFK-1: phosphofructokinase-1; PI3K: phosphoinositide 3-kinase; PPAR-γ: peroxisome proliferator-activated receptor gamma; ROS: reactive oxygen species; STAT3: signal transducer and activator of transcription 3; TGF-β1: transforming growth factor beta 1; TNF-α: tumor necrosis factor alpha and VEGF: vascular endothelial growth factor.

Figure 4

Mechanism of action of rhein. Abbreviations: APC: adenomatous polyposis coli; CDK: cyclin-dependent kinase; Dsh: dishevelled; EMT: epithelial to mesenchymal transition; ERK: extracellular signal-regulated kinase; GSK3β: glycogen synthase kinase 3β; HIF-1α: hypoxia-inducible factor 1 alpha; JAK: Janus kinase; MEK: mitogen-activated protein kinase kinase; MMP: matrix metalloproteinase; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa light chain enhancer of activated B cells; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; and STAT: signal transducer and activator of transcription.