ReviewProtein kinases as targets for developing anticancer agents from marine organisms
Introduction
Protein kinases catalyze the transfer of a phosphate group to a specific amino acid in a protein, affecting its specific functions. Over the past years, more than five hundred different protein kinases have been identified [1]. According to their selectivity toward substrates, protein kinases are divided into several subfamilies mainly including tyrosine protein kinases, serine threonine protein kinases etc. [2]. Protein kinases function as important cellular regulators, and are involved in regulating cell proliferation, apoptosis, motility as well as DNA damage-repair, etc. [3]. Protein kinases such as PI3K, Akt, MAPK, and EGFR, are commonly activated and/or highly expressed in cancer cells, acting as activators in carcinogenesis. In most cases, protein kinases play a central role in the networks of signal transduction, and thus are considered as important targets for discovery and the development of novel anticancer agents [4]. In the past decades, numerous proteins kinase inhibitors have been discovered and developed, and some of them have been successfully applied clinically. Protein kinase inhibitors now account for a quarter of all newly discovered and developed drugs. Gefitinib (Iressa), a selective EGFR inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of non-small cell lung cancer in 2015 [5,6]. Sorafenib (Nexavar; Onvx/Bayer), a multi-target tyrosine kinase inhibitor, was approved by FDA for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer in 2005 [[7], [8], [9]]. However, the off-target and drug resistance of protein kinase inhibitors limit their efficacy and application for the treatment of cancer patients. Therefore, there are urgent needs for finding novel agents overcoming the weakness of protein kinase inhibitors.
The marine environment is characterized for being extremely harsh and exposed to different life conditions such as lack of light, extreme pressure, highly salt concentration. Therefore, marine organisms have undertaken adaptive mechanisms and symbiotic interactions different from terrestrial species. Organisms living in the sea synthesize a wide variety of chemicals used as defense for predators [10]. The biodiversity of marine organisms provides a rich source for the discovery and development of novel anticancer agents in the treatment of human malignancies. Compared with other biological compounds, some of the components from marine organisms display more potent cytotoxicity. Structurally, some types of compounds like cyclic peptides, bromophenols, and polyketones are mostly found in marine organisms [11]. Over the years, an increasing number of novel compounds with anticancer activity have been isolated from marine organisms, and many of them have been reported to possess promising anticancer activity via inhibition of protein kinase mediated signaling pathways (Fig. 1). Marine-derived compounds provide additional opportunities for discovering novel kinase inhibitors with special targets on the kinase pathway [12]. Actually, several protein kinase inhibitors from a marine origin have entered clinical trials and displayed promising results for the treatment of human cancer. Recently, Li et al. reviewed the protein kinase inhibitors from marine source and listed the marine compounds by the species of marine organisms [13]. In this review, we presented the compounds isolated from marine organisms according to their mode of actions on protein kinases and the progress as anticancer agents. The marine compounds targeting special pathways of protein kinases were highlighted. The problems and prospect for discovering and developing anticancer agents from marine organisms were also discussed.
Section snippets
Components isolated from marine organisms targeting P13K/Akt/mTOR pathway
The P13K/Akt/mTOR signal transduction pathway plays an important role in the development of a variety of tumors such as breast cancer, colorectal cancer, liver cancer etc., and activation of the signaling pathway is commonly found in most kinds of malignancies. Over the past years, several components isolated from marine organisms were found to induce cell death via inhibiting P13K/Akt/mTOR pathway.
SNL (1) (Fig. 2), a cembrane-based diterpenoid, was isolated from cultured-type soft coral
Discussion
Table 1 summarized the components isolated from marine organisms and their main targets in protein kinases signaling pathways. However, it should be emphasized that some of the compounds can target multiple signaling pathways related to protein kinases. For examples, 10 can inhibit the p38 MAPK and NF-κB pathways besides targeting the PI3K/Akt signaling pathway; treatment of cancer cells with 10 can result in inhibition of the phosphorylation of MAPKs and increase of Bax/Bcl-2 ratio regulated
Conclusions
Marine organisms are rich source for finding natural anticancer compounds. Due to the peculiar life of these organisms in the sea, some of the compounds like bromophenols, desipeptides are mostly found in marine sources. However, studies on the marine natural products as anticancer and other pharmaceutical purposes are still in the stage of infancy. More marine products with anticancer activity could be found from the marine organisms with the advancement of modern deep-sea technology. One
Author contributions
Material preparation and writing—original draft preparation, K.B.; writing—review and editing, G.Q., M.P., J.L., and X.L.; investigation and resources, M.L.; visualization, M.L., and G.Q.; project administration, funding acquisition, conceptualization and supervision, X.L., M.P., C.S. and J.L. All authors have read and agreed to the published version of the manuscript.
Funding
The study was supported by the National Science Foundation of China (No# 81573457, #81773776). We are also grateful for the support by the Taishan Talents project of Shandong Province and the Department of Science and Technology in Shandong Province of China (No#: ZR2017MH117 and 2018YYSP025, ZR2017MH027), Department of Science and Technology in Sichuan of China (No#: 2017HH0104, and 2019YFS0116), as well as the International Collaborative Project of the MOST of China (No#: 2017YFE0195000).
Declaration of Competing Interest
All of the authors declared no conflict of interest.
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These authors contributed equally to this work.