2021, Vol. 20
表1(Table 1)
2) Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, 646000, China
The PI3K/Akt/mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signaling network have been tested in clinical trials involving patients with a range of different cancers (Janku et al., 2018). The clinical developments of many of these agents, however, have not advanced to late-phase randomized trials due to toxicity (Song et al., 2010). Presently, the mTOR inhibitors temsirolimus and everolimus and the PI3K inhibitors idelalisib and copanlisib have been approved by the FDA for clinical use in the treatment of a number of different cancers (Willis et al., 2020). Novel compounds with greater potency and selectivity, as well as improved therapeutic indices with reduced toxicity, are clearly required. In addition, biomarkers that are predictive of a response, such as PIK3CA mutations for inhibitors of the PI3K catalytic subunit α isoform, must be identified and analytically and clinically validated (Wu et al., 2020). Finally, considering that oncogenic activation of the PI3K/Akt/mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signaling networks, rational combinations are also needed to optimize the effectiveness of treatment.
Marine organisms are rich sources for finding natural anticancer compounds. Due to their particular lifestyles in the sea with a special environment, some of the compounds such as bromophenols and depsipeptides are mostly found in marine sources. The biodiversity of marine organisms provides a rich source for the discovery and development of novel anticancer agents in the treatment of human malignancies (Zheng et al., 2018). Organisms living in the sea synthesize a wide variety of chemicals used as defense for predators (Wang et al., 2020). Compared with other biological components, some of the components from marine organisms display more powerful cytotoxicity. Over the years, an increasing number of novel compounds with anticancer effects have been isolated from marine organisms, and many of them have been reported to possess promising anticancer activity via inhibition of PI3K-mediated signaling. In this mini-review, we presented those compounds isolated from marine organisms with inhibitory effects on the PI3K/Akt/mTOR signaling. The challenges and prospects for developing anticancer agents using the PI3K/ Akt/mTOR signaling as target were also discussed.
2 Components Isolated from Marine Organisms Targeting the PI3K/-Akt/mTOR PathwayAs a natural carotenoid, fucoxanthin (Fig. 1) is isolated from seaweed, and the compound exhibits a broad spectrum of biological activities, including anti-inflammatory (Heo et al., 2010), anti-mutagenic (Tanaka et al., 2012), and anticancer activities (Nishino, 1995; Satomi, 2017). Fucoxanthin is capable of inhibiting the growth of a number of cancer cells, including liver cancer (Liu et al., 2009, 2013; Satomi and Nishino, 2009), colon cancer (Hosokawa et al., 2004; Liu et al., 2012), leukemia (Ishikawa et al., 2008; Yamamoto et al., 2011), prostate cancer (Satomi, 2012) and bladder cancer (Wang et al., 2012). It has been demonstrated that inactivation of the PI3K/Akt signaling is an important event in fucoxanthin-induced cancer cell apoptosis; treatment with fucoxanthin (1 μmol L-1) led to down regulation of the p-PI3K, p-Akt significantly in HeLa cancer cells (Ye et al., 2014). Additionally, exposure of human glioma U251 and U87 cancer cells with fucoxanthin (50 μmol L-1) resulted in an inhibitory effect of the Akt/ mTOR signaling and the compound also inhibited the migration and invasion of the cancer cells (Liu et al., 2016). ROS production is an important event in fucoxanthininduced inhibitory effect on the invasion and migration of glioma cells; the inhibitory effect of the compound on cancer cell growth was diminished in the presence of antioxidant glutathione (Wu et al., 2019). Recent study also found that fucoxanthin was capable of increasing the cytotoxicity of cisplatin; in the presence of fucoxanthin, the cell viability was markedly suppressed compared with that of cisplatin alone and the combination of fucoxanthin and cisplatin also increased the ratio of Bax/Bcl2 (Liu et al., 2013).
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Fig. 1 Chemical structures of compounds, isolated from marine organisms, targeting PI3K/Akt/mTOR signaling pathway. |
Marine sponges are recognized as one of the most productive sources of anticancer components, and a lot of bioactive compounds with anticancer activity have been found from marine sponges (Bader et al., 2005). Stellettin B (Stel B, Fig. 1) belongs to an isomalabaricane triterpene. It has been extracted from marine sponge Jaspisste llifera. Previous study indicated that the compound was capable of inducing apoptosis via the PI3K/Akt/mTOR signaling pathway in cancer cells. Stel B treatment induced apoptosis via enhancing the production of ROS, the cleavage of PARP, as well as inhibiting the activity of caspase 3/7 in human glioblastoma SF295 cells (Tang et al., 2014). Recent study showed that Stel B is able to inhibit the phosphorylation of PI3K and Akt in SF295 cells (1 μmol L-1) and human chronic myeloid leukemia K562 cells (0.036 μmol L-1) (Chen et al., 2017). Moreover, Stel B also leads to the ROS generation and increased expression of PARP in NSCLC cells (Hsiao et al., 2016). It can also induce G1 arrest via inhibiting the expression of cyclin D1 and increasing the expression of p27 (Cheng et al., 2019). The PI3K/Akt/mTOR signaling pathway also plays a role in Stel B-induced (1 μmol L-1) apoptosis in A549 cells. Additionally, Stel B treatment results in down-expression of PI3K-p110 and inhibitory of the phosphorylation of PDK1, Akt, mTOR, and p70S6K (Hsiao et al., 2016).
In 1988, Roll et al. isolated an alkaloid fascapysin from marine sponge Fascaplysinopsis sp. (Roll et al., 1988). Recent study showed that its synthesized derivative 4-chloro fascaplysin (4-CF, 3 μmol L-1, Fig. 1) exhibited potent antiangiogenetic activity via blocking the PI3K/Atk/mTOR pathway (Sharma et al., 2017). Treatment with 4-CF resulted in downregulation of VEGF and Akt in HUVEC cells, while in the presence of the inhibitors of VEGF and Akt (sunitinib and perifosine), the cytotoxic effect of 4-CF was significantly inhibited in HUVEC cells.
Sinulariolide (SNL, Fig. 1), a cembrane-based diterpenoid, was isolated from cultured-type soft coral Sinularia flexibilis (Neoh et al., 2012). Previous studies have shown that SNL possesses anticancer effects by inducing apoptosis in several cancer cells; SNL treatment led to activation of caspase cascade in A375 melanoma cells (Li et al., 2013). Recent studies showed that the PI3K/Akt signaling played an important role in SNL-induced (10 μg mL-1) cancer cell apoptosis in cancer cell invasion and migration via inhibiting the phosphorylation of PI3K, Akt and mTOR (Wu et al., 2015). In order to increase the efficiency of the compound, SNL was modified by conjugating with HA (hyaluronan) nanoparticles to form a novel complex compound HA/SNL aggregates. Since hyaluronan nanoparticles possesses high hydrophilicity, the bioavailability of the compound was greatly increased, and HA/SNL displays more powerful anticancer effect than SNL (Hsiao et al., 2016).
As an anticancer alkaloid, staurosporine (Fig. 1) was originally isolated from a terrestrial Streptomyces sp. (Omura et al., 1977). The compound was also isolated from several other marine Streptomyces sp. (Cartuche et al., 2019; Pimentel-Elardo et al., 2010). Staurosporine was capable of inducing apoptosis in human pancreatic carcinoma PaTu 8988t and Panc-1 cells. Staurosporine treatment resulted in decreased expression of Bcl-2 and Bad. The PI3K/Akt signaling plays an important role in staurosporine-induced cancer cell apoptosis. Treatment with staurosporine (20 nmol L-1) can inhibite the Akt phosphoralytion significantly in HepG2 cells (Ding et al., 2017). To increase the anticancer activity, several derivatives of staurosporine were synthesized. Enzastaurin (Fig. 1) is one of the derivatives. It can inhibit the cancer cell growth with potent activity and higher water solubility (Faul et al., 2003). Enzastaurin (3.56 μmol L-1) can inhibit the proliferation of gastric cancer both in vitro and in vivo via affecting the Akt signaling cascade (Lee et al., 2008). Preclinical study showed that enzastaurin inhibited the growth of a panel of small-cell lung cancer lines. Enzastaurin treatment led to G1 arrest and apoptosis by suppressing the PKC/ERK 1/2 pathway in uveal melanoma cells carrying GNAQ mutation (Öztaşkın et al., 2015), and resulted in downregulation of the phosphorylation of GSK3βSer9, ribosomal protein S6Ser240/244, and AktThr308 significantly in xenogeneic glioblastoma cells. Enzastaurin also displays antiangiogenesis activity by downregulating VEGF (vascular endothelial growth factor) and suppressing the microvessel density in human tumor xenograft-bearing nude mice (Keyes et al., 2004). The safety of enzastaurin was confirmed by phase Ⅰ clinical study for patients with refractory solid tumors and lymphoma. Oral administration of 500 mg of enzastaurin once daily were well tolerated (Li et al., 2016). phase Ⅰ clinical trial of the compound showed promise as minimal toxicity was demonstrated. However, phase Ⅱ and phase Ⅲ clinical trials is disappointing for patients with diffuse B cell lymphoma (Robertson et al., 2007), relapsed and refractory mantle cell NSCLC (Oh et al., 2008) and lymphoma (Morschhauser et al., 2008). Therapy of enzastaurin with other chemotherapeutic agents were developed; the combination of enzastaurin with bevacizumab for the treatment of recurrent malignant gliomas was well-tolerated, with similar results to bevacizumab monotherapy (Odia et al., 2016). Synergistic effects were also found using the combination of enzastaurin and Ibrutinib in the treatment of large B cell lymphoma (He et al., 2019).
Bromophenols, a large class of marine natural products, are widely distributed in various marine organisms including marine sponges, algae, cyanobacteria and marine fungi (Wang et al., 2013; Blunt et al., 2018). Bromophenols exhibits broad biological activities such as antibacterial activities, antivirus and anticancer activity (Liu et al., 2011; Öztaşkın et al., 2015; Wang et al., 2015). Shi's laboratory developed a series of bromophenol derivatives and one of the bromophenol derivatives BOS-102 (Fig. 1) displayed potent anticancer effect toward several human cancer cell lines especially for human lung cancer cells. Treatment with BOS-102 resulted in apoptosis and cell cycle arrest in lung cancer A549 cells. BOS-102 was able to activate caspase-3 and PARP, enhance the Bax/Bcl-2 ratio, increase the ROS generation, and decrease ΔΨm, leading cytochrome release from mitochondria. Recent study revealed that the PI3K/Akt pathway was involved in the cancer cell apoptosis induced by BOS-102 (10 μmol L-1). Treatment with the compound resulted in downregulation of the phosphorylation of PI3K and Akt significantly in A549 cells (Guo et al., 2018).
Bostrycin (Fig. 1) found in marine fungi Nigrospora sp. in the South China Sea is able to inhibit the growth of prostate and gastric cancer (Yang et al., 2012; Fan et al., 2018). Studies have shown that bostrycin (10 μmol L-1) can suppress the proliferation of human lung carcinoma A549 cells via downregulation of the PI3K/Akt signaling. Treatment with bostrycin downregulated the levels of p-Akt significantly, while the levels of p27 were up-regulated, leading to cell cycle arrest at G1 phase (Chen et al., 2011).
As a sulfated polysaccharide compound, fucoidan (Fig. 1) was originally found in the cell wall matrix of many kinds of brown seaweeds (Li et al., 2008). Fucoidan possesses a broad spectrum of bioactivities including antivirus, antibacterial and anti-cancer activities. In recent years, increasing attention is focused on the anti-cancer effect of fucoidan since the compound exhibits potent anticancer effect with low toxicity (Lee et al., 2004; Aisa et al., 2005; Gideon and Rengasamy, 2008; Yamasaki-Miyamoto et al., 2009; Yang et al., 2013). The PI3K/Akt signaling is involved in fucoidan-induced cancer cell apoptosis in a number of cancer cells. Treatment with fucoidan (200 μg mL-1) suppressed the cell migration and viability significantly in HT-29 cells (Han et al., 2015). Fucoidan can also inhibit the growth of human breast cancer MDA-MB-231 cells by downregulating the expressions of p-PI3K, p-Akt, and p-GSK3β (Xue et al., 2017). Recent study also found that fucoidan was capable of suppressing the cell viability and inducing the apoptosis in human prostate PC-3 cancer cells via inhibiting the PI3K/Akt signaling pathway (Boo et al., 2013). Fucoidan-induced cancer cell apoptosis and cell cycle arrest are not associated with p53 expression. Treatments of the p53 positive and negative HCT-116 cells with fucoidan result in similar apoptosis and DNA damage (Park et al., 2017).
Xyloketal B (Fig. 1) is obtained from mangrove fungus Xylaria sp. in the South China Sea (Lin et al., 2001). The compound exhibits antioxidant activity and protective effects on endothelial and neuronal oxidative injuries. Xyloketal B (300 μmol L-1) is capable of inhibiting the growth of glioma cells. The PI3K/Akt signaling is involved in the regulation of proliferation and migration of glioblastoma cells (Yajima et al., 2012). Treatment with xyloketal B leads to the downregulation of p-Akt and p-ERK1/2 significantly in human glioma U251 cancer cells (Chen et al., 2015).
3 DiscussionIn the present mini-review, we discussed the compounds isolated from marine organisms and their main targets are the PI3K/Akt/mTOR signalling (Table 1). However, it should be emphasized that some of the compounds can target multiple pathways. Except for targeting the PI3K/ Akt signaling, fucoxanthin can also suppress the p38 MAPK and NF-κB pathways; treatment with fucoxanthin can inhibit the phosphorylation of MAPKs, and increase the expression of NF-κB-regulated Bax/Bcl-2 ratio (Kumar et al., 2013). ROS-mediated oxidative damage plays a role in fucoxian-induced cancer cell apoptosis (Jang et al., 2018). The PI3K/Akt/mTOR pathway is also involved in inflammatory event. The fucoxanthin can decrease pro-inflammatory cytokines, such as IL-1b, IL-6, and TNF-α, by suppressing NO production and iNOS expression (Heo et al., 2010). Moreover, fucoxanthin can significantly inhibit the inflammation of mice with paw edema by suppressing the levels of NO and Akt in the plasma. It can protect catalase (CAT) and superoxide dismutase (SOD) against disruption in mice with paw edema (Choi et al., 2016). More studies are needed to address if there is correlation between the anticancer activity and anti-inflammatory effects of fucoxanthin.
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Table 1 The compounds isolated from marine organisms and their main targets on the PI3K/Akt/mTOR signaling pathway |
In the past decades, significant progress has been made in developing anticancer agents targeting the PI3K signalling. However, the toxicity and the drug resistance hinder the clinical application of these drugs. Several approaches overcoming the drug resistance are developing. It is important to find novel agents targeting alternative binding sites on the signalling factors or targeting the other pathways that are required for activating the PI3K signaling (Gumireddy et al., 2005). Future studies should focus on finding novel compounds from marine organisms with low toxicity and targeting special sites on the PI3K/Akt signaling. As the special marine environment provides the diversity of marine natural products to offer unique anticancer agents with promising clinical value, it is worthy to identify more anticancer agents that can be used clinically.
AcknowledgementsThe study was supported by the National Natural Science Foundation of China (Nos. 81573457 and 81773776). We are also grateful to the support from the Taishan Talents Project of Shandong Province and the Department of Science and Technology in Shandong Province of China (Nos. ZR2017MH117, 2018YYSP025, and ZR2017MH 027), and Department of Science and Technology of Si-chuan Province, China (Nos. 2017HH0104 and 2019YFS 0116).
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