Targeting cancer with sesterterpenoids: the new potential antitumor drugs

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.


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 (C 5 ), monoterpenoids (C 10 ), sesquiterpenoids (C 15 ), diterpenoids (C 20 ), sesterterpenoids (C 25 ), triterpenoids (C 30 ), tetraterpenoids (C 40 ), and polyterpenoids (more than C 40 ) [7,8]. Among these terpenoids, pharmaceutical effects against tumor cells have been extensively reported in monoterpenoids and triterpenoids [9][10][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][13][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 promising candidates for anticancer drugs [7,8,15]. However, their functional mechanisms and molecular targets are barely known to date.
Sesterterpenoids commonly harbor C 25 carbon skeletons in their molecular structures. However, some compounds that contain C 21 -C 24 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.

Bicarbocyclic sesterterpenoids and their cytotoxicities against tumor cells
Sesterterpenoids with a bicarbocyclic skeleton in many compounds show structures reminiscent of the clerodane and labdane diterpenoids [7,8]. Kohamaic acid A (34) [32], a compound isolated from Ircinia species of marine sponge, functions as a powerful inhibitor of DNA polymerases [32], which are specialized for DNA replication and repair, and can help cancer cells tolerate DNA damage [33]. Some of these enzymes have been developed as viable targets for therapeutic strategies of cancer [33]. The derivatives of kohamaic acid A have also been shown to prevent the growth of HL-60 human cancer cells through inhibition of DNA replication and repair processes [34]. Several sesterterpenes, including thorectandrols A-D (35-38) [35,36] and palauolol (39) [37], share similar chemical structures and also display cytotoxicities against a variety of cancer cell lines [38]. Palauolol shows significant inhibitory activity against MCF-7, SNB-19, COLO-205, KM12, MOLT-4, H460, A549, LOX, and MALME-3 tumor cell lines, whereas thorectandrols A-D only display weak activities against some of them [38]. Two other sesterterpenoids (40 and 41), which were isolated from the Coscinoderma species of sponge, exhibit moderate cytotoxicities against K562 cells [39] (Fig. 3).
Moreover, scalaradial (80) and cacospongionolide A (98) should be particularly noted; they are isolated from Cacospongia scalaris and Fasciospongia cavernosa marine sponges, respectively, and can significantly inhibit the growth of T47D, A431, HeLa, and HCT116 cells with different mechanisms [57]. Detailed studies indicate that treatment of T47D cells with scalaradial or cacospongionolide can lead to increased DNA migration and fragmentation [57]. Incubation of HCT116 and HeLa cells with scalaradial or cacospongionolide results in increased pro-apoptotic protein levels and the loss of mitochondrial transmembrane [57], implying the activation of apoptosis signaling. These results suggest that scalaradial and cacospongionolide may represent new promising compounds for inhibiting cancer cell proliferation (Fig. 5). Studies also demonstrate that miscellaneous sesterterpenoids exhibit significant cytotoxicities against tumor cells. Salmahyrtisol A (99), which was isolated from Hyrtios erecta, exhibits significant cytotoxicity against murine leukemia (P-388), A-549, and HT-29 human cancer cells [58]. Terpestacin (100), a miscellaneous compound, was isolated from a Phomopsis species of fungus [59]. Mechanistic study indicates that terpestacin suppresses tumor angiogenesis by targeting UQCRB of mitochondrial complex III in the mitochondrial respiratory chain, thereby causing the inhibition of hypoxia-induced reactive oxygen species and cellular oxygen sensing [59,60] (Fig. 6).

Chemical structure-activity relationships
Some sesterterpenes share similar chemical structures but exhibit distinct cytotoxic activities against cancer cells. Thus, it will be interesting and helpful to investigate the relationship between chemical structure and activity. Although many sesterterpenes have been found to show cytotoxicities to tumor cells, it is impossible to compare their activities meaningfully since different cancer cell lines were used for different compounds in cytotoxic assays. Here, we track some sesterterpenes isolated by Dr. Liu's group (from South China Sea Institute of Oceanology) in the past years, and try to find factors affecting their activities (Table 1), thereby providing guidance for modifying the chemical structure of sesterterpenes and obtaining derivatives with more bioactivity in the future.

C-21 structures and cytotoxicities against tumor cells
Sarcotin A, a compound isolated from Sarcotragus species, possesses a pair of epimers, C-21R (101) and C-21S (102) [61]. Cytotoxicity analysis indicates that the C-21R epimer is much more cytotoxic than the C-21S epimer. Consistent with this, sarcotin B (103) and isopalinurin (104), and the other two furanosesterterpenes (105 and 106) from Psammocinia species also show much higher cytotoxicity to cancer cells in their C-21R epimers than their respective C-21S epimers [62] (Fig. 7) c-Hydroxybutenolide moiety and cytotoxicities against tumor cells Some cacospongionolides (98, 107-108) share similar chemical structures with thorectandrols, but exhibit significantly higher cytotoxicities than thorectandrols. Their structure comparison suggests a possible relationship between the c-hydroxybutenolide moiety and cytotoxicity [57,63]. Furthermore, some sesterterpenes including a norsesterterpenoid compound (109), sarcotin I (110) and sarcotin J (111) [61,64], share similar chemical structures with compound 101. However, their cytotoxicities against cancer cells are weaker than compound 101, which contains a c-hydroxybutenolide moiety. These results clearly demonstrate that the c-hydroxybutenolide moiety is necessary for the activities of sesterterpenes, and the opening ring of c-hydroxybutenolide may also cause the decrease in cytotoxicity (Fig. 8).

Furan moiety and cytotoxicities against tumor cells
The furan moiety also displays a relevance to cytotoxicity. Comparison of the chemical structures and cytotoxicities of compounds 109 and 112-113 indicates that sesterterpenes containing a furan moiety have increased cytotoxicity when the furan moiety is oxygenated to form unsaturated lactone or dihydrofuran [63,64]. Moreover, sesterterpenes 8 and 114-117 containing two furan moieties show higher cytotoxicities than those compounds (118-120) that contain only one furan moiety [65]. That is to say, the more furan rings means stronger cytotoxicities, and the oxidation of a furan ring at an appropriate degree might also improve the cytotoxicities of sesterterpenes (Fig. 9).

Pyrrole moiety and cytotoxicities against tumor cells
The pyrrolosesterterpenes are chemically unique compounds, and incorporate a pyrrole ring to replace the furan ring. The pyrrole moiety also displays correlation with cytotoxicity in sesterterpenes. Comparison of the chemical structures and activities of compound 118 and sesterterpenes 121-126 indicates increased cytotoxicity in compounds harboring a pyrrole moiety [61]. However, sesterterpenes carrying a b-substituted lactam ring (127) instead of the a-substituted one exhibit dramatically decreased activity [61]. Moreover, an alkyl moiety attached on the N-atom of the pyrrole ring is also required for cytotoxicity. For instance, some sesterterpenes (128-131), in which the alkyl moieties are substituted by carboxylic acid sodium, show completely absent cytotoxicity [64] ( Fig. 10).

Double bonds and cytotoxicities against tumor cells
The double bonds within the sesterterpenes also have significant effects on cytotoxicity, and the effect is complicated. For instance, comparison of cytotoxicities of two furanosesterterpenes (9 and 10) isolated from a Psammocinia species of marine sponge [60] clearly indicates that compound 10 which carries a double bond in D 12,13 has much higher cytotoxicity than 9 [60]. Furthermore, the configuration of double bonds also plays important roles for the activities of compounds. Some E-difuranosesterterpenes (115 and 117) have been reported to display lower activities than their respective Z-difuranosesterterpenes (114 and 116) [65]. The different position of double bonds may lead to different activities. For instance, compounds 105 and 106 share similar structures, but have different positions of double bonds. Interestingly, compound 105 exhibits higher cytotoxicity than 106 in SK-MEL-2, SK-OV-3, and XF498

Challenges and future directions
One challenge for cancer chemotherapy is the lack of effective antitumor drugs. The traditional chemotherapeutic medicines cannot selectively kill cancer cells, and consequently cause serious side effects including immuno- logical, neurological, metabolic, and infectious diseases. Developing compounds from natural sourcea as anticancer drugs is a new strategy to overcome or decrease these side effects. Interestingly, many sesterterpenoids from natural sources have been reported to exhibit strong cytotoxicities by inhibiting cancer cell proliferation and/or inducing cell death. These sesterterpenoids are attracting more interest and may represent new promising compounds in cancer therapy. Although many sesterterpenoids have been reported to exhibit significant cytotoxicities in vitro, few studies have provided insights into their molecular targets and mechanisms. Thus, it is necessary to further explore studies on signal transduction involved in cancer pathways, the in vivo physiological roles and the systematic structureactivity relationships of these compounds. The detailed mechanistic understanding of sesterterpenoids may provide critical insights into future development and investigation of cancer therapeutics with higher specificity and selectivity. The commendable understanding of relationship between structures and activities can, in turn, help us to chemically modify and synthesize powerful compounds against tumor cells. Furthermore, we anticipate establishing a sesterterpenoid compound-bank to screen effective and specific compounds against various diseases, including but not limited to cancer. Sesterterpenoids may be used in combination with other chemotherapeutic drugs to increase effectiveness and decrease doses of individual compounds, therefore reducing side effects.