Targeting cancer with sesterterpenoids: the new potential antitumor drugs

J Nat Med (2015) 69:255–266 DOI 10.1007/s11418-015-0911-y REVIEW Targeting cancer with sesterterpenoids: the new potential antitumor drugs Caiguo Zhang1 • Yan Liu2 Received: 26 January 2015 / Accepted: 3 April 2015 / Published online: 19 April 2015 Ó The Japanese Society of Pharmacognosy and Springer Japan 2015 Abstract Cancer remains a major cause of death in the world to date. A variety of anticancer drugs have been used in clinical chemotherapy, acting on the particular oncogenic abnormalities that are responsible for malignant transformation and progression. Interestingly, some of these anticancer drugs are developed from natural sources such as plants, marine organisms, and microorganisms. Over the past decades, a family of naturally occuring molecules, namely sesterterpenoids, has been isolated from different organisms and they exhibit significant potential in the inhibition of tumor cells in vitro, while the molecular targets of these compounds and their functional mechanisms are still obscure. In this review, we summarize and discuss the functions of these sesterterpenoids in the inhibition of cancer cells. Moreover, we also highlight and discuss chemical structure–activity relationships of some compounds, demonstrating their pervasiveness and importance in cancer therapy. Keywords Terpenoids
Sesterterpenoids
Cancer therapy
Structure–activity relationship & Yan Liu Caiguo Zhang 1 Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA 2 State Key Laboratory of Photochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China Introduction: overview of sesterterpenoids and their biological functions Natural compounds sourced from different organisms exhibit immense structural diversity and possess extensively biological activities against malaria, inflammation, multiple types of cancer, and many infectious diseases. Many of these compounds have been used in clinical therapy, such as etoposide [1], vincristine [2], irinotecan [3], and paclitaxel [4]. As the largest subclass of natural products, accounting for more than 40,000 individual compounds, terpenoids also exhibit diverse biological functions, particularly in the prevention and therapy of multiple cancer types such as skin, lung, pancreatic, colon, and prostate cancer [5, 6]. Based on the number of isoprene units building their parent terpene scaffold, terpenoids can be generally categorized into hemiterpenoids (C5), monoterpenoids (C10), sesquiterpenoids (C15), diterpenoids (C20), sesterterpenoids (C25), triterpenoids (C30), tetraterpenoids (C40), and polyterpenoids (more than C40) [7, 8]. Among these terpenoids, pharmaceutical effects against tumor cells have been extensively reported in monoterpenoids and triterpenoids [9–11], which exhibit the ability to suppress the growth of cancer cells by inducing tumor cell differentiation and apoptosis, and inhibiting tumor angiogenesis, invasion, and metastasis [12–14]. In recent years, sesterterpenoids, a small subgroup of terpenoids, have been widely isolated from different organisms, and also exhibit diverse biological properties involving anti-inflammatory, antimicrobial, anti-feedant, antitubercular, and anti-biofilm formation [7, 8]. Some sesterterpenoids even possess multifunctional activities. For instance, manoalide has both anti-inflammatory and antimicrobial activities [7, 8]. Importantly, many sesterterpenoids can suppress the growth of cancer cells in vitro, and are therefore considered as 123 256 promising candidates for anticancer drugs [7, 8, 15]. However, their functional mechanisms and molecular targets are barely known to date. Sesterterpenoids commonly harbor C25 carbon skeletons in their molecular structures. However, some compounds that contain C21–C24 are also grouped into sesterterpenoids, termed as norsesterterpenoids [7, 8]. So far, nearly 1,000 sesterterpenoids have been isolated from terrestrial fungi, lichens, higher plants, insects, and various marine organisms, particularly sponges [8, 16]. Based on the carbocycle numbers contained in their molecular structures, sesterterpenoids can be broadly classified into 6 subgroups: linear, monocarbocyclic, bicarbocyclic, tricarbocyclic, tetracarbocyclic, and miscellaneous sesterterpenoids [7, 8, 17]. All of these six subclasses of sesterterpenoids have been reported to exhibit significant cytotoxicities against tumor cells. Linear sesterterpenoids and their cytotoxicities against tumor cells Although the structures of linear sesterterpenoids are very simple, many of them possess significant cytotoxicities against human tumor cells, with unknown mechanisms of action. Four C22 furanosesterterpenoids isolated from the Ircinia species of sponges, including irciformonins C (1), D (2), 15-acetylirciformonin B (3), and 10-acetylirciformonin B (4) [18], have been reported to significantly inhibit different human cancer cells, in which compounds (1) and (2) Fig. 1 Structures of linear sesterterpenoids 1–12 123 J Nat Med (2015) 69:255–266 suppress the growth of colon tumor cells, and compounds (3) and (4) display notable cytotoxic activities against K562, DLD-1, HepG2, and Hep3B cancer cells [8, 19]. Some haslenes (5–7) (from Haslea ostrearia) that house C25 highly branched isoprenoid (HBI) alkenes appear to possess cytostatic effects on human lung cancer cells in vitro [20, 21]. Four furanosesterterpenes isolated from the marine sponge Ircinia oros, ircinin-1 (8) [22], (7E, 12E, 18R, 20Z)-variabilin (9) [23], (8E, 13Z, 18R, 20Z)-strobilinin (10) [23], and (7E, 13Z, 18R, 20Z)-felixinin (11) [23], have been demonstrated to show cytotoxicities against SK–MEL-2 human cancer cells by inducing cell cycle arrest and apoptosis [8, 22]. Supplementation with ircinin-1 (8) can lead to G1 phase arrest during cell cycle progression, and this process is associated with a marked decrease in protein levels of cyclin D, CDK4 and CDK6 [22]. Ircinin-1 can also induce the release of cytochrome c, activation of caspase-3 and caspase-9, and upregulation of Fas and Fas-L [22]. Moreover, furospinosulin-1 (12), a marine-spongederived furanosesterterpene, exhibits activity against DU145 human prostate cancer cells by inhibiting cell proliferation [24]. Subsequent study has demonstrated that furospinosulin-1 could suppress the expression of insulinlike growth factor-2 (IGF-2) [24], which is a hypoxia-inducible angiogenic factor and is selectively induced under hypoxic conditions through inhibiting the binding of nuclear proteins to the Sp1 consensus sequence in the IGF-2 promoter region [24] (Fig. 1). J Nat Med (2015) 69:255–266 Monobocyclic sesterterpenoids and their cytotoxicities against tumor cells A variety of monobocyclic sesterterpenoid compounds have also been demonstrated to exhibit significant cytotoxicities. However, little is known about their functional mechanisms. (...truncated)