The use of tumor angiogenesis as a therapeutic target is based on extensive literature showing the dependence of tumors on the process of angiogenesis for growth, invasion, and metastasis. Seminal work performed by Folkman three decades ago determined that tumors beyond the size of approximately 2 mm require angiogenesis for subsequent growth and development. This basic hypothesis stimulated research in the field of angiogenesis and has resulted in the identification of factors that both enhance and inhibit this "angiogenic switch.
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SargA, a sulfated heteropolysaccharide extracted from the brown marine alga Sargassum stenophyllum , was also reported to exhibit antiangiogenic activity in vitro and in vivo Table 1 [ 57 , ]. The xanthones anomalin A and norlichexanthone Figure 3 can be isolated from the sponge-derived fungus Arthrinium sp.
This may be one of the reasons why anomalin A could inhibit VEGF-A dependent endothelial cell sprouting whereas norlichexanthone could not [ ].
All three compounds showed tyrosine kinase inhibitory activity and could elicit antiangiogenic effects in assays for the proliferation, migration, and tube formation of endothelial cells [ ].
Ten marine-derived angiogenesis inhibitors entered clinical trials for cancer therapy, but 5 of them failed in different stages. The phase III clinical trials of the shark cartilage extract neovastat [ 94 , 95 , 96 ] and the phase II clinical trials of the tubulin inhibitor soblidotin [ , ] failed due to the lack of the expected therapeutic efficacy. Therefore, we here only discuss the clinical data of the other five marine-derived angiogenesis inhibitors, i.
Since , over 80 separate phase I and II clinical trials for cancer therapy using bryostatin-1 alone or in combination with conventional anticancer drugs have been conducted [ 8 ]. Different types of human cancers have been investigated in these clinical studies, including chronic lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, melanoma, renal cell carcinoma, colorectal cancer, soft tissue sarcoma, head and neck cancer, ovarian cancer, cervix carcinoma, gastric cancer, gastroesophageal cancer, esophageal cancer and pancreatic carcinoma [ 79 , , , , , , , , , , , , , , , , , , , , , ].
Although the precise mechanism of bryostatintriggered myalgia remains unknown, it could be manageable by some measures such as exercise, taking analgesics, and dose control. Nevertheless, myalgia is still an important reason for ending clinical studies [ ]. In particular, the combination of bryostatin-1 with paclitaxel, cisplatin or vincristine in phase II clinical studies produced promising therapeutic effects [ , , , ]. Therefore, bryostatin-1 is possible to prevent or delay the occurrence of tumor MDR to the combined drug s such as paclitaxel or vincristine [ ].
On the other hand, the toxicities of the combinations would not increase compared with those of their separate uses [ 75 ]. To reduce this risk, it may need to develop appropriate molecular biomarkers for the selection of patients and the therapeutic surveillance in its clinical studies and potential uses. In addition, although the antiangiogenic activity of bryostatin-1 was shown in preclinical studies, it was not reported in any clinical trials.
So it could not be concluded whether the antiangiogenic activity practically contributes to the clinical anticancer effects of bryostatin According to the present clinical results, the clinical development of bryostatin-1 is faced with several major challenges, including how to reduce its toxicity mainly myalgia , increase its therapeutic efficacy mainly through combination with other anticancer drugs , and develop proper molecular biomarkers for the selection of patients and the therapeutic surveillance.
Another problem is its very limited yield from natural resources. Moreover, it is also hard to be synthesized [ 75 ]. However, because of its unique PKC modulation and anticancer activity, more potent analogues of bryostatin-1 deserve testing in the clinical arena. The marine-derived angiogenesis inhibitor panobinostat is among the most potent HDAC inhibitors [ ]. It is undergoing extensive phase I and phase II clinical trials with clinical studies [ ].
Panobinostat is orally or intravenously available [ ]. The major toxicities of panobinostat in humans are hematologic including thrombocytopenia, neutropenia, anemia and leukopenia , fatigue, and gastrointestinal nausea and diarrhea but generally manageable [ , , , , , , , ]. Although phase II clinical trials of panobinostat have been conducted in solid e.
However, the response of multiple myeloma to panobinostat monotherapy was just modest [ , ]. The combination of panobinostat with other anticancer drugs could expand its potential clinical applications. Its combination with paclitaxel and carboplatin reported in a phase I study [ ] was well tolerated. In contrast, the combination of panobinostat, bevacizumab and everolimus was not tolerable [ ].
The results are interesting because all panobinostat, paclitaxel and carboplatin can inhibit bone marrow but both bevacizumab and everolimus have very limited hematologic adverse effects. The results suggest that the toxicity of these combinations may have additional determinants and careful selection of its combined drugs is very important. The results also suggest that in addition to histone hyperacetylation, other biomarkers more relevant to the clinical therapeutic efficacy and toxicity of panobinostat are urgently needed [ ].
Phase I results show that plitidepsin has a unique toxicity profile that is similar in children and adult cancer patients [ ]. Its main dose-limiting toxicities are muscular and hepatic toxicities. The most common muscular toxicities are myalgia and asthenia with unknown mechanisms, and co-treatments with l -carnitine can prevent them or accelerate their recovery [ , , ].
Its hepatic toxicities are transaminase increases but generally reversible. Other toxicities of plitidepsin include fatigue, pyrexia, skin rash, abdominal pain, nausea, vomiting and diarrhea. Of note, plitidepsin does not significantly inhibit bone marrow at pharmacological concentrations [ , ]. Moreover, it does not seem to produce cross-resistance between plitidepsin and other conventional anticancer drugs [ ].
Phase II studies with plitidepsin monotherapy further confirmed its favorable safety profile, but did not demonstrate significant clinical anticancer activity in solid tumors such as unresectable advanced medullary thyroid carcinoma [ ], refractory advanced malignant melanoma [ ], pretreated small cell lung cancer [ ] and pretreated non-small cell lung cancer [ ]. In contrast, the recently released results of a phase II study with single-agent plitidepsin revealed its clinical activity with an overall response rate of Plitidepsin showed synergistic activity with rituximab in preclinical models of diffuse large cell and Burkitt lymphoma [ ].
Its combination with dexamethasone in a phase II clinical trial also displayed therapeutic efficacy though limited [ ]. Therefore, future clinical development of plitidepsin might predominantly test for its therapeutic efficacy against hematological malignancies, preferentially through combination with other anticancer drugs. Preclinical data indicate that marizomib inhibits all three enzymatic activities of the proteasome with preferential inhibition of the chymotrypsin-like and trypsin-like proteasome enzymes.
Therefore, marizomib could overcome the resistance to bortezomib that selectively inhibits the chymotrypsin-like activity of the proteasome. In addition, this broader spectrum of enzymatic activity inhibition is also likely to confer a differential anticancer spectrum and a different toxicity profile to marizomib. This unique feature provided the basis for the clinical development of marizomib although bortezomib has been approved for clinical uses [ ].
Marizomib is undergoing phase I clinical trials. The results available indicate its safety and preliminary anticancer activity. Notably, marizomib did not cause myelosuppression neutropenia and thrombocytopenia or peripheral neuropathy that could be related to bortezomib. In addition, the combination with the HDAC inhibitor vorinostat did not enhance the toxicity of marizomib but could synergistically increase its therapeutic efficacy in patients with melanoma, pancreatic and lung cancer [ , , ].
With marizomib monotherapy, stable disease was observed in patients with multiple myeloma, melanoma, cervical, colorectal, hepatocellular, adenoid cystic, granulosis cell or ovarian carcinoma [ , ]. Taken together, marizomib is well tolerated with a unique toxicity profile and has demonstrated preliminary therapeutic effects, which warrants its further clinical development. The tubulin inhibitor plinabulin is a vascular disrupting agent, two phase I trials of which have been reported.
In contrast, the second one tested the combination of plinabulin with docetaxel in 13 patients with advanced non-small cell lung cancer, gastrointestinal stromal tumor, liposarcoma or melanoma [ 25 ].
The results showed its favorable safety profile with fatigue, tumor pain, nausea, diarrhea and vomiting as the most common but manageable adverse events. Fever, tumor pain, and transient hypertension were also observed. One dose limiting toxicity of nausea, vomiting, dehydration and neutropenia occurred. Drug-related neurologic toxicity or myelosuppression was not significant. Importantly, the combination of plinabulin and docetaxel did not increase their respective toxicities [ 25 , ].
These phase I trials also demonstrated its antitumor activity. Its combination with docetaxel led to a partial response in two patients and decreased tumors in four patients among total eight evaluable patients with non-small cell lung cancer [ 25 ].
These results support its further clinical development of either monotherapy or combination. With the successful clinical uses of angiogenesis inhibitors and marine-derived anticancer drugs for cancer therapy, the development of marine-derived antiangiogenic agents is attracting more and more attention.
To date, dozens of marine natural products and their synthetic analogues have been shown to inhibit angiogenesis or to disrupt established blood vessels, and several of them are undergoing anticancer clinical trials with encouraging results. Moreover, with the increasing exploration of marine sources, new marine angiogenesis inhibitors will continue to be found and developed, which will possibly offer more choices to the clinic for cancer therapy in future. National Center for Biotechnology Information , U.
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Abstract Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Keywords: marinenatural products, angiogenesis, protein kinase, cancer therapy. Introduction Angiogenesis not only plays an important role in physiological processes but is also involved in initiating and promoting several diseases such as cancer. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Cytoskeleton Disturbing Agents Microtubule and actin are the major structural compositions of cytoskeleton that is involved in many important cellular events including cellular shape, mitosis, movement, signaling transduction and substance transportation.
Table 1 Assays used to test for angiogenesis inhibitory activity of agents reviewed in this paper. Others There are additional marine natural products that show antiangiogenic activity in different models the tube formation assay was used most widely Table 1 but via unique or unknown mechanisms. The PKC Activator Bryostatin-1 The PKC family contains at least 12 isozymes characteristic of different structures, functions, subcellular localization, and substrate specificity. Cortistatin A Cortistatins Figure 2 are a family of eleven steroidal alkaloids isolated from the marine sponge Corticium simplex.
Neovastat The antiangiogenic activity of neovastat, an extract from shark cartilage, has been widely investigated. Aeroplysinin-1 Aeroplysinin-1 Figure 4 is a marine-derived brominated tyrosine metabolite that has antibacterial, antiparasitic, anticancer and antiangiogenic activities.
Philinopside A and Philinopside E Both are sulfated saponins isolated from the sea cucumber Pentacta quadrangulari. Ageladine A The brominated pyrrole-imidazole alkaloid Ageladine A Figure 2 was first isolated from the marine sponge Agelas nakamurai but now can be obtained by synthesis using different methods [ , , , , ].
Saccharides Several marine-derived saccharides, mainly from sea algae, have been reported to inhibit tumor angiogenesis, which is related to their TK inhibition.
Anomalin A and Norlichexanthone The xanthones anomalin A and norlichexanthone Figure 3 can be isolated from the sponge-derived fungus Arthrinium sp.
Clinical Trials of Marine-Derived Angiogenesis Inhibitors for Cancer Therapy Ten marine-derived angiogenesis inhibitors entered clinical trials for cancer therapy, but 5 of them failed in different stages.
The PKC Activator Bryostatin-1 Since , over 80 separate phase I and II clinical trials for cancer therapy using bryostatin-1 alone or in combination with conventional anticancer drugs have been conducted [ 8 ].
The Proteasome Inhibitor Marizomib Preclinical data indicate that marizomib inhibits all three enzymatic activities of the proteasome with preferential inhibition of the chymotrypsin-like and trypsin-like proteasome enzymes.
The Tubulin Inhibitor Plinabulin The tubulin inhibitor plinabulin is a vascular disrupting agent, two phase I trials of which have been reported. Conclusions With the successful clinical uses of angiogenesis inhibitors and marine-derived anticancer drugs for cancer therapy, the development of marine-derived antiangiogenic agents is attracting more and more attention. Conflict of Interest The authors declare no conflicts of interest related to this work.
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