Abstract (as presented by the authors of the scientific work):
"Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, -gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA2s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed."
Conclusions and future directions (as presented by the authors of the scientific work):
"AA cascade, a metabolic pathway, has been found to have involvement in cancer initiation, promotion and progression. Roles of AA metabolizing enzymes and their products have been well characterized in cancer progression and development. Several chemical carcinogens, UV-radiation, tobacco, and proinflammatory cytokines are involved in carcinogenesis by activating multiple pathways, including AA cascade. PLA2s are a group of enzymes which initiate AA cascade by acting on membrane-bound phospholipids to form LPLs and AA. Further, the released AA is oxygenated by variety of oxygenases, including COXs, LOXs and CYP dependent monoxygenases to form bioactive signaling oxylipids like PGs, LTs and epoxy/hydroxy- eicosatrienoic acids respectively.
sPLA2s are first identified PLA2 isoforms and their roles in cancer have not been well characterized. Accumulated literature suggests that GIIA, GV and GX sPLA2s have key roles in inflammation, but several studies have demonstrated the anti-tumor activities of several sPLA2s isoforms. The role of sPLA2s in cancer is thus controversial and further investigations are required. Among GIV(A-F) cPLA2 isoforms, GIVA cPLA2 plays an important role in initiation and progression of inflammation and cancer and it can be a novel chemopreventive and therapeutic target. Several research findings suggested that iPLA2 is also involved in carcinogenesis, but it has been characterized as housekeeping enzyme. LPLA2 is also necessary for normal physiological functions. Lp-PLA2 does not have significant involvement in cancer. Surprisingly, AdPLA exhibits tumor-suppressive activity.
COX has two important isoforms COX-1 and COX-2. COX-1 is a constitutive enzyme but COX-2 expression is observed in several cancers. As the conventional NSAIDs inhibit both COX-1 and COX-2, they were found to have many side effects as a result of inhibition of cytoprotective COX-1. In this scenario, COX-2 selective inhibitors (COXIBs) have been believed to be safe drugs. However, their clinical utility has been hampered due to their side effects. Several synthetic COX-2 inhibitors were withdrawn from the market due to their severe adverse effects. Although most of the pro-tumorigenic activity of COX-2 is attributed to the generation of PGE2, it is important to highlight that the other COX-2-derived products can also affect tumor development. Accumulating evidences suggest that EP(1-3) have pro-tumorigenic roles in several cancers and their antagonists/genes suppressors can be potential chemopreventive agents. Recent findings suggest that COX-2 and PGs have key role in the development of drug resistance in cancer patients undergoing chemotherapy. In this scenario, inhibition of COX-2 pathway could be a potential strategy to overcome the drug resistance problem. 5-LOX and its major metabolic product, LTB4, have been characterized as novel chemopreventive targets for cancers among other LOX isoforms. Moreover, BLT1&2, receptors for LTB4 have been characterized as protumorigenic mediators. In this context, antagonists for BLT1&2 can be developed as novel chemopreventive agents.
Recent findings suggest that pathway diversion is a major problem in targeting the AA pathway. For instance, COX-2 pathway inhibition caused shunting AA metabolism towards the LOX or CYP pathways. In the same way, 5-LOX inhibition caused shunting AA metabolism towards the COX-2 or CYP pathways. In addition, recently identified HK pathway linked with both 5-LOX and COX-2. Hence, blocking two major pathways involved in carcinogenesis, namely the 5-LOX and COX-2 pathways, can be a plausible approach to better inhibit cancer progression. At the same time, PLA2 initiates the AA cascade and inhibition of PLA2 prevents the liberation of AA and LPLs. Hence, researchers have been considering PLA2s to be a better therapeutic target than the downstream enzymes, namely COX-2 and 5-LOX. However, a fundamental problem in drug development is diversity and redundancy in PLA2 isoforms. Moreover, complete physiological roles of PLA2 isoforms are not clearly known. However, several recent findings suggest that inhibition of AA specific-GIVA cPLA2 is advantageous as it is upstream to COX-2 and 5-LOX and prevents liberation of AA and LPLs. Overall, multi-targeting of AA pathway is highly advantageous for effective prevention and/or treatment of several cancers.
Realizing the role of AA pathway in several cancers, considerable efforts are being made to the discovery and development of inhibitors of AA pathway as cancer preventive and therapeutic agents. NSAIDs have been explored as chemopreventive agents for several cancers. However, several side effects associated with usage of NSAIDs hampered their clinical applications. Natural products have a much better safety profile than synthetic molecules. In this context, research on AA pathway inhibitory natural products has gained momentum to develop them as novel chemopreventive and therapeutic agents. Apigenin (1), anthocyans (2), baicalein (3), berberine (4), curcumin (5), diallyl sulfides (6), ellagic acid (7), epigallocatechin gallate (8), eugenol (9), fisetin (10), garcinol (11), genistein (12), -gingerol (13), guggulsterone (14), indole-3-carbinol (15), lycopene (16), nordihydroguaiaretic acid (17), C-phycocyanin (18), piperine (19), quercetin (20), resveratrol (21), silibinin (22), sulforaphane (23), thymoquinone (24), triptolide (25), ursolic acid (26) and wogonin (27) are some of the important AA pathway targeting natural products which have been identified from natural sources and these are under development as cancer chemopreventive and therapeutic agents at various stages, including their clinical development.
Curcumin, berberine and garcinol blocked multiple COX-2, LOXs and cPLA2 pathways, thereby exhibiting chemopreventive and therapeutic potentials against several cancers. Resveratrol exerted chemopreventive activity by blocking COX-2, LOX and CYP pathways. Thymoquinone, garcinol, lycopene and piperine exhibited dual 5-LOX and COX-2 inhibitory activities. Baicalein showed chemopreventive and anti-cancer activities against several cancers by inhibiting 12-LOX. NDGA exhibited anti-cancer activities by inhibiting the activities of 5-LOX, and other LOXs. Apigenin, cyanidin-3-glucoside, delphinidin, curcumin, diallyl sulfide, fisetin, -gingerol, resveratrol, silibinin, and wogonin prevented UVB radiation-induced skin carcinogenesis by inhibiting COX-2 pathway. Curcumin, guggulsterone and indole-3-carbinol blocked tobacco and its constitutents-induced inflammation and carcinogenesis by down-regulating COX-2. Apigenin, curcumin, genistein, -gingerol, gugglosterone, piperine, resveratrol, silibinin, sulforaphane and ursolic acid prevented chemically-induced tumorigenesis by targeting COX-2 pathway. Berbeine and ellagic acid suppressed cPLA2 expression while garcinol prevented activation of cPLA2 by inhibiting its phosphorylation. Curcum suppressed cPLA2 expression and prevented cPLA2 activation by inhibitiong MAPK-mediated phosphorylation. Rosmarinic acid reported to possess sPLA2 and COX-2 inhibitory activities. Several PLA2-inhibitory natural products have been identified, but their anti-cancer efficacy has not been examined systematically. Metabolic pathway diversion is a major problem in development of AA pathway inhibitors. Seveal studies suggest that either COX-2 or LOX inhibitor are ineffective in countering inflammation and thus inflammation-induced carcinogenesis. Recently we have isolated COX and 5-LOX dual inhibitory compounds dammarane triterpeniod 1 and chebulagic acid from seed coat of B. flabellifer and fruits of T. chebula respectively, and found their anticancer and pro-apoptotic potentials in cancer cells. Also COX-2 and 5-LOX dual inhibitors have been developed by several other groups which are at different stages of clinical development. Futher in vivo anticancer, toxicity and pharmacokinetic studies are required for their clinical developemnt.
Natural products, in genral, are known to exhibit better safety profile in toxicity studies and are non-mutagenic and non-genotoxic in nature. Curcumin is characterized as non-toxic and “Generally Recognized As Safe” (GRAS) by the US FDA. However, recently a committee of the FDA voted to prohibit its use intravenously due to inadequate evidence of safety or efficacy. This decision is not yet law in the US, and is currently being challenged. Recent reports on genotoxic effects of -gingerol are controversial and need futher investigations. Anthocyans are less toxic with anti-oxidant and anti-genotoxic potentials. The available data is not sufficient to conclude that anthocyans are less/non toxic. Further, a detailed and long-term toxicity studies on anthocyans are required. NDGA was once classified as “Generally Recognized As Safe” by US FDA but later this classification was withdrawn due to its toxicity concerns. NDGA was not overtly toxic at low doses. However, high doses of NDGA have been associated with several adverse effects. Further detailed studies are necessary to get clarity on toxic effect of NDGA which is a major problem in clinical use of NDGA. Eugenol, a cancer chemopreventive agent, exhibits genotoxic and carcinogenuc properties. Aspirin eugenol ester, a hybrid molecule, shows comparable anti-inflammatory activity with aspirin and eugenol, but it is no or less toxic. Resveratrol, curcumin, ellagic acid, silibinin and thymoquinone exhibit protective effects against xenobiotic-induced toxicity in addition to their safety profile in toxicity studies. C-Phycocyanin containing water extract of Spirulina, generally recognized as safe by US FDA, is a promising agent as potent anti-oxidant, anti-inflammatory, chemopreventive and chemotherapeutic agent for variety of cancers. However, its high molecular weight and delivery problems limit its further development as a clinical agent. Hence there is need for identifying a fragment of this biliprotein without loosing its therapeutic properties.
Bioavailability of the natural products is a major problem for their clinical development. Several nano-particle based drug delivery methods have been explored for improvement of bioavailability of natural products. Also several analogs of the natural products have been synthesized with enhancement of their bioavailability as well as improving therapeutic potentials. Aspirin, acetyl ester of salicylic acid, is the most successful anti-inflammatory drug developed as a natural product analog targeting COXs. Several analogs of the natural products have been synthesized with enhancement of their bioavailability. Internal metabolization is one of the reasons for low bioavailability of curcumin, resveratrol and other natural products. Piperine enhances the bioavailability of curcumin as well as resveratrol by inhibiting internal metabolization of these phytochemicals.
Combinatorial therapy using AA pathway-inhibitory natural products may also be advantageous not only for improving the chemopreventive efficacy, but also useful in overcoming the several problems, including bioavailability and drug resistance. Combinations of piperine with curcumin or resveratrol caused enhancement of bioavailability of both compounds and exhibit better chempeventive efficacy. Combinations of indole-3-carbinol and silibinin effectively prevented carcinogen-induced lung tumorigenesis in mouse by suppressing pro-inflammatory and pro-carcinogenic mediators, including COX-2, than alone. Ursolic acid in combination with resveratrol effectively prevented TPA-induced skin tumor promotion by suppressing inflammatory mediators, including COX-2. Several studies proved that eugenol and combination with sulforaphane or gemcitabine can be useful for chemoprevention of cervical cancer. Lycopene and fish oil acted synergistically as chemopreventive agents against colon carcinogenesis by blocking COX-2 pathway. Therefore, various combination/formulation of AA pathway-inhibitory natural products may be useful to improve its efficacy towards cancer prevention and therapy.
Drug resistance is a major problem in current chemotherapy for cancers. We and others have suggested that COX-2 and PGs have key roles in drug resistance in cancer and their inhibitors can be useful to reverse the drug resistance and sensitize the chemoptherpeutic drugs. C-phycocyanin, a COX-2 selective inhibitor, inhibited MDR1-mediated drug resistance in HepG2 cells. Drug resistance-inhibitory potency of C-phycocyanin was due to its COX-2 inhibition activity and by inhibiting ROS generation. Similarly it was shown by several investigators have shown that celecoxib and guggulsterone overcome imatinib resistance and induces apoptosis in imatinib-resistant leukemic cells by inhibiting COX-2 and P-glycoprotein. Hence, researchers may explore COX-2 inhibitory natural products as sensitizers of drugs and/or inhibitors of drug resistance.
Overall, research on development of AA pathway inhibitory natural products in cancer prevention and therapy is in good progress. Safety profile of AA pathway inhibitory natural products in toxicity studies represents an advantage for their clinical development. However, poor bioavailability of the AA pathway inhibitory natural products is a major problem for their clinical development as cancer chemopreventive and therapeutic agents. At the same time, several alternative strategies have been developed by several investigators to enhance the bioavailability of some of the natural products. In this context, discovery of new inhibitors of AA pathway from natural sources as well as a detailed investigations including clinical evaluation on existing AA pathway inhibitory natural products are needed for their development as effective and safe drugs for cancer prevention and therapy."
Dhananjaya BL, Dowluru KS, Chintala R, Duddukuri GR.
Targeting arachidonic acid pathway by natural products for
cancer prevention and therapy. Semin Cancer Biol.
2016 Oct;40-41:48-81. doi: 10.1016/j.semcancer.2016.02.001.
Prof. Atanas G. Atanasov (Dr. habil., PhD)