Open Access This article is
- freely available
Molecules 2019, 24(5), 995; https://doi.org/10.3390/molecules24050995
Pleiotropic Pharmacological Actions of Capsazepine, a Synthetic Analogue of Capsaicin, against Various Cancers and Inflammatory Diseases
KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
Comorbidity Research Institute, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
Authors to whom correspondence should be addressed.
Academic Editor: Roberto Fabiani
Received: 18 February 2019 / Accepted: 8 March 2019 / Published: 12 March 2019
Capsazepine is a synthetic analogue of capsaicin that can function as an antagonist of TRPV1. Capsazepine can exhibit diverse effects on cancer (prostate cancer, breast cancer, colorectal cancer, oral cancer, and osteosarcoma) growth and survival, and can be therapeutically used against other major disorders such as colitis, pancreatitis, malaria, and epilepsy. Capsazepine has been reported to exhibit pleiotropic anti-cancer effects against numerous tumor cell lines. Capsazepine can modulate Janus activated kinase (JAK)/signal transducer and activator of the transcription (STAT) pathway, intracellular Ca2+ concentration, and reactive oxygen species (ROS)-JNK-CCAAT/enhancer-binding protein homologous protein (CHOP) pathways. It can inhibit cell proliferation, metastasis, and induce apoptosis. Moreover, capsazepine can exert anti-inflammatory effects through the downregulation of lipopolysaccharide (LPS)-induced nuclear transcription factor-kappa B (NF-κB), as well as the blockage of activation of both transient receptor potential cation channel subfamily V member 1 (TRPV1) and transient receptor potential cation channel, subfamily A, and member 1 (TRPA1). This review briefly summarizes the diverse pharmacological actions of capsazepine against various cancers and inflammatory conditions.
Keywords:capsazepine; cancer; inflammatory diseases; ROS; TRPV1
Capsaicin (8-Methyl-N-vanillyl-trans-6-nonenamide) is the commonly found pungent ingredient in hot chili peppers [1,2]. Capsaicin can act as a pharmacological agent that can regulate inflammation and pain using specific receptors of afferent sensory neurons . The transient receptor potential vanilloid type 1 (TRPV1) channel can be activated by capsaicin . TRPV1 is a ligand-gated non-selective, cation channel, and it was first reported in sensory neurons such as dorsal root ganglion (DRG) . As soon as the TRPV1 channel is activated, uptake of calcium (Ca2+) ion is rapidly increased . Ca2+ plays an important role in diverse signal transduction pathways , including cell proliferation, cell death, neural excitation, neurotransmitter release, etc.
Capsazepine(N-[2-(4-Chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2 carbothioamide) is a synthetic analogue of capsaicin . It was first discovered and characterized by the Sandoz (now Novartis) , and it was modified on the chemical backbone of capsaicin , (Figure 1). Interestingly, capsazepine (10 µM) can also reversibly reduce the response to capsaicin (500 nM) of voltage-clamped DRG neurons in rats . Moreover, capsazepine can act as a potent blocker of TRPV1 channels. It can bind to the pores of transmembrane domain on TRPV1 channel and can interact with all monomers residues of this channel . Capsazepine can also exhibit several pharmacological effects via blocking TRPV1 channel and thereby suppressing the influx of Ca2+ . It can thus be effectively used for the prevention and treatment of various cancers and inflammatory conditions, although its clinical use has been hampered, owing to its poor pharmacokinetic properties (Figure 2).
Additionally, capsazepine has been also reported to target various other receptors including other TRP channels such as TRPV4 and TRPM8 [7,8,9]. It can also block nicotinic acetylcholine receptors and voltage-activated calcium channels in rats [7,8]. Interestingly, Docherty et al. reported that capsazepine can mediate human hyperpolarization-activated cyclic nucleotide-gated two and four channels and inhibit currents in the HEK293 cells concentration dependently . This finding can also partly explain the reported anti-nociceptive effects of capsazepine .
2. Pharmacological Actions of Capsazepine in Tumor Cell Lines
2.1. Anti-Cancer Effects of Capsazepine In Vitro
Several compounds derived from Mother Nature can function as potent anti-cancer agents that can abrogate the process of tumorigenesis [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Capsazepine has been reported to exert significant anti-proliferative effects against multiple tumor types in vitro, as summarized in Table 1. The mechanisms underlying the anti-cancer/growth inhibitory effects include the inhibition of activation of Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, calcium ion influx, ROS-JNK-CHOP pathway, and modulation of other important signal transduction pathways (Figure 3).
2.1.1. Prostate Cancer
Signal transducer and activator of transcription (STAT) proteins activation associated with cell proliferation, survival, and angiogenesis [27,31,32,33,34,35,36,37,38,39,40]. STAT3 is frequently hyper-activated in tumor cells and regulates the expression of oncogenic genes . Capsazepine was found to induce substantial apoptosis in DU145 and PC-3 prostate cells by inhibiting STAT3 activation . The suppression of STAT3 was caused through the inhibition of upstream Janus activated kinase-1, 2 (JAK1, JAK2), and c-Src kinases. Moreover, capsazepine induced the expression of PTPε both protein and mRNA levels that may mediate the STAT3 inhibitory effects of the drug . Capsazepine also decreases the expression of various oncogenic proteins, invasion, and promoted apoptosis in prostate cancer .
While capsazepine has been known to be a potent blocker of the TRPV1 channel. Huang et al. reported that capsazepine can exhibit anticancer effects in prostate cancer by inducing intracellular Ca2+ concentration. There are two different ways to store Ca2+. For example, IP3-sensitive Ca2+ stores release Ca2+ into the cytosol when cells are stimulated by an endogenous agent, whereas IP3-insensitive Ca2+ stores can release Ca2+ into the cytosol when cells are stimulated by the exogenous agent . Human PC-3 cells can store Ca2+ in the endoplasmic reticulum . Capsazepine induced intracellular Ca2+ concentration by Ca2+ influx, and thereby releasing Ca2+ from the endoplasmic reticulum . Interestingly, capsazepine causes the release of Ca2+ from the endoplasmic reticulum in a phospholipase C independent manner as the U73122, an inhibitor of phospholipase C, treatment did not significantly effect capsazepine-induced Ca2+ release .
2.1.2. Breast Cancer
System xc− (xCT), the functional unit of cys-tine/glutamate antiporter, has been found to be elevated in many tumor types in response to high ROS concentrations . When this antiporter is upregulated, it can promote cell survival by inducing cysteine uptake and promoting glutathione (GSH) production . High glutamate released by System xc− (xCT) has been associated with cancer-induced bone pain (CIBP) during distal breast metastasis . The exchange of cystine for glutamate generally occurs at a stoichiometric ratio of 1:1 induced by the intracellular concentration of glutamate . Therefore, the inhibition of System xc− (xCT) can induce the downregulation of glutamate release, and thus reduce mechanical hyperalgesia associated with CIBP . Capsazepine was found to significantly inhibit System xc− (xCT) by blocking the uptake of cysteine . Capsazepine was also found to induce ROS production, which led to a substantial programmed cell death in MDA-MB-231 cells .
2.1.3. Colorectal Cancer
TNF-related apoptosis-inducing ligand (TRAIL) has the role of anti-cancer effects . TRAIL can bind to the death receptors and activate the extrinsic apoptotic cell death pathway [5,41,42,43,44]. TRAIL can induce cancer apoptosis by increasing the activation of death receptors DR4 and DR5. DR induction has been related to the increased activation of CCAAT/enhancer-binding protein homologous protein (CHOP), ROS production, as well as to the augmented JNK phosphorylation [45,46]. Interestingly, capsazepine was found to induce TRAIL receptor expression by upregulating both DR4 and DR5 receptors through JNK activation in colorectal HCT116 cells . It also required ROS and CHOP to exert these effects . Capsazepine also decreased the expression of cell survival proteins and increases the pro-apoptotic proteins .
2.1.4. Oral Cancer
Gonzales et al. reported that capsazepine can exhibit both cytotoxic and anti-tumor effects in oral squamous cell carcinoma (OSCC) . These effects were associated with the production of ROS independently of its action on the TRPV1 channel . ROS can regulate the activation of various signaling molecules including NF-κB, STAT3, JNK, hypoxia-inducible factor-1α, kinases, growth factors, cytokines and other proteins, and enzymes [29,35,38,47,48,49,50,51,52]. It has been closely linked to cell proliferation, survival, invasion, and metastasis of cancer [48,53]. It is well known that cancer cells undergo oxidative stress due to increased metabolic activity resulting in a subtle balance between ROS levels and cellular antioxidant capabilities. When ROS levels are increased above basal level, the subtle balance may be disrupted and thus trigger ROS induced apoptosis. Vanilloids such as capsazepine have been found to increase ROS and thus alter the balance between normal ROS contents and cellular antioxidant capabilities [29,54,55]. Capsazepine was also observed to augment apoptosis in a concentration-dependent manner in SCC4, SCC25, and HSC3 cells .
Capsazepine can also exert potent anti-cancer effects on MG63 osteosarcoma cells . Capsazepine can induce intracellular Ca2+ increase by causing extracellular Ca2+ influx . Moreover, capsazepine can cause intracellular Ca2+ release from endoplasmic reticulum via a phospholipase C-independent manner . It was also noted to attenuate cell proliferation in a concentration dependent manner . The multiple oncogenic targets modulated upon capsazepine treatment are briefly summarized in Figure 3.
2.2. Anti-Cancer Effects of Capsazepine In Vivo
2.2.1. Prostate Cancer
Capsazepine has been reported to exhibit anti-cancer effects in prostate cancer in preclinical settings . Capsazepine administered at doses of 1 mg/kg and 5 mg/kg three times a week for up to 20 days abrogated tumor growth in the xenograft prostate cancer mouse model . Additionally, capsazepine treatment caused reduction in phosphorylation of STAT3 and increased PTPε protein levels in tumor tissues .
2.2.2. Breast Cancer
2.2.3. Oral Cancer
Capsazepine treatment in oral squamous cell carcinoma (OSCC) xenograft mouse model was observed to attenuate tumor growth . HSC3, SCC4, and SCC25 xenografts were treated with 0.02, 0.04 mg capsazepine for 12, 16, or 18 days, respectively. Anti-tumor effects of capsazepine has no adverse effects on non-malignant tissues in vivo  (Table 2).
3. Effects of Capsazepine on Inflammatory Conditions
Lipopolysaccharide (LPS) can interact with Toll-like receptor 4 (TLR4), leading to the activation of nuclear transcription factor-kappa B (NF-κB), a transcription factor that plays an important role in both inflammation and cancer [56,57,58,59,60,61,62,63,64,65,66,67]. NF-κB can initiate the transcription of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), and other pro-inflammatory mediators . Nitric oxide (NO) is one of the key products generated during an inflammatory response [69,70]. Capsazepine can downregulate NO production by attenuating iNOS mRNA expression in LPS-stimulated RAW264.7 macrophages . Capsazepine was also found to abrogate LPS-induced NF-κB activation and it was noted that these inhibitory effects were mediated via its antioxidant activity .
Capsazepine is an effective blocker at TRPV1 in human, rat, and guinea pig. Capsazepine can block the TRPV1 responses in response to low pH and heat in human and guinea pig with a better efficacy than in rat . Additionally, capsazepine has been reported to reduce both inflammatory and neuropathic mechanical hyperalgesia in guinea pigs, but not in rats 
Sensory neurons have two major polymodal ion channel receptors, TRPV1 and transient receptor potential ankyrin 1 (TRPA1) . Sensitization of both TRPA1 and TRPV1 can lead to hyperalgesia and both channels can also exert neurogenic inflammatory effects . TRPA1 was found in DRG and has an important role in peripheral pain . TRPA1 can also exert anti-inflammatory and anti-nociceptive effects similar to TRPV1 . Kistner et al. found that capsazepine can also exhibit inhibitory effects on colitis via the modulation of TRPA1 . They demonstrated this hypothesis by using capsazepine-induced calcium transients in human TRPA1-expressing HEK293t cells and mice . The diverse pro-inflammatory mediators affected by capsazepine treatment are depicted in Figure 4 (Table 3).
Attenuation of experimental colitis by capsazepine has been attributed to its antagonistic effects on TRPV1channel, and were also found to be associated with the inhibition of neurogenic inflammation . For example, repeated capsazepine administration can attenuated trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats . Rats were treated with 37.7 × 10−5 mg/kg/day of capsazepine enema for six days . Capsazepine was found to downregulate macroscopic damage score (MDS) and MPO scores . Similarly, capsazepine can prevent intestinal inflammation in dextran sulphate sodium (DSS)-induced colitis . Sprague-Dawley rats were treated with 0.1 mg/kg/day for six days . Capsazepine significantly decreased the levels of disease activity index (DAI), myeloperoxidase (MPO) activity in DSS-induced colitis .
TRPV1 activation was also found to be involved in acute pancreatitis. Wick et al. reported that the sensory nerves that stimulate pancreas can release TRPV1, substance P (SP), and CGRP in dorsal horn caused during the nociception process . Antagonism of TRPV1, SP, and CGRP receptors can inhibit pancreatitis pain . Additionally, pancreaticobiliary duct obstruction may cause an increase in the pancreatic leukotriene B4 (LTB4) concentrations . It can thus mediate TRPV1 activation and causes acute pancreatitis. Rats were pre-treated with capsazepine 37.7 × 10−3 mg/kg sc 30 min before surgery . Capsazepine caused a downregulation of various inflammatory parameters such as myeloperoxidase (MPO) activity, pancreatic edema, and histological damage in leukotriene B4 (LTB4)-induced pancreatitis .
Malaria is an infectious disease caused by the bite of infectious mosquitoes and the outcome of infection depends on the host’s innate immune response . White et al. investigated the role of TRPV1 in malaria for the first time and employed C57BL/6 mice treated with capsazepine 0.05 mg/kg/day for six days . They found that capsazepine was able to regulate the innate immune response to malaria in mice infected with Plasmodium berghei ANKA .
Calcium ion accumulation in hippocampal neurons is a major contributor to epilepsy . Ghazizadeh et al. and Naziroglu et al. investigated that epilepsy effects on oxidative stress [83,84]. They found that Ca2+ signaling and the apoptosis in pentylentetrazol (PTZ)-induced hippocampal injury in rats. Shirazi et al. reported that TRPV1 receptors are important for PTZ and amygdala-induced kindling in rats . TRPV1 antagonist, capsazepine can modulate epileptiform activity by anti-convulsant properties . During epilepsy induction, intracellular calcium ion concentration was found to be increased . Capsazepine caused a decrease in intracellular Ca2+ concentration . There are many studies anti-epileptic effect of capsazepine [6,27,80,86,87]. Gonzalez-Reyes et al. reported that the capsazepine administration can suppress 4-AP induced ictal activity and propagation of seizure activity in vitro (10–100 µM) and in vivo (50 mg/kg s.c.) . In addition, capsazepine can act directly on the axons through the blood brain barrier . Nazıroğlu et al. has also shown that capsaicin-induced TRPV1 sensitization can cause Ca2+ elevation, thereby increasing apoptosis and epileptic seizures . These processes were reduced by capsazepine (0.1 mM) treatment . Additionally, capsazepine can potentiate the anti-nociceptive effects of morphine in mice . Morphine treatment can induce TRPV1 expression in the DRG, spinal cord upon repeated exposure . Interestingly, TRPV1 antagonists can be used effectively as pharmacological agents against morphine treatment. Santos et al. found that capsazepine treatment can lead to an inhibitory avoidance, thereby leading to a decrease in the rat elevated plus-maze test and thus indicating that TRPV1 may have a key role in regulating anxiety . Similarly, a decreased expression of TRPV1 channels and inhibitory avoidance behavior was observed in rats that received capsazepine in the elevated plus-maze test  (Table 4).
3.5. Neurogenic Inflammation
Capsazepine can inhibit neurogenic inflammation mediated by TRPV1 [89,90]. Inflammatory responses caused by the release of inflammatory mediators such as neuropeptide calcitonin gene-related peptide (CGRP) and substance P (SP) from primary afferent nerve terminals are referred to as neurogenic inflammation [89,91]. Inflammatory neuropeptides release by antidromic activation of afferent nociceptors and dorsal root reflexes (DRRs) play a key role in this process . Flores et al. reported that capsazepine (300 μL) abolished the capsaicin-evoked release of immunoreactive CGRP (iCGRP) in Sprague-dawley rats buccal mucosa . Moreover, the neurosecretion of capsaicin-evoked iCGRP via the vanilloid receptor mediated mechanism .
Further, capsazepine can inhibit H2S-induced neurogenic inflammation [89,90,93]. Hydrogen sulfide (H2S) is a mediator of diverse biological effects . It also contributes to local and systemic inflammation . Sodium hydrogen sulfide (NaHS) used as a donor of H2S and induces sensory nerve activation in the guinea pig airways . Capsazepine can abrogate NaHS evoked neuropeptide release through desensitization of TRPV1 . Bhatia et al. noted that capsazepine pretreatment (15 mg/kg) in mice can protect H2S-inducing lung inflammation . Additionally, they found that H2S is located upstream of TRPV1 activation, and can regulate the release of sensory neuropeptides in sepsis .
4. Conclusions and Future Perspectives
In this article, we have briefly reviewed diverse pharmacological actions of capsazepine in vitro and in vivo. Capsazepine can exert therapeutic effects against various malignancies and inflammatory disorders. It can suppress proliferation and metastasis, induce apoptosis by modulating several oncogenic signaling pathways, and thereby exert its anti-tumoral effects in different cancers. Moreover, capsazepine can reduce the levels of inflammatory mediators such as DAI, and MPO activity, however, the concentrations at which it can exert these pleiotropic anti-tumoral/anti-inflammatory effects may vary depending on the cell types and in vivo model systems used for investigation. Additional studies are required to elucidate the unmet potential of capsazepine in suitable animal models and clinical settings.
M.H.Y. and S.H.J. conceived the project and wrote the manuscript. G.S. and K.S.A. edited the manuscript.
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2018R1D1A1B07042969).
Conflicts of Interest
The authors declare no conflict of interests.
|TRPV1||Transient receptor potential vanilloid type 1|
|DRG||Dorsal root ganglion|
|STAT||Signal transducer and activator of transcription|
|JAK1, JAK2||Janus activated kinase-1, 2|
|CIBP||Cancer-induced bone pain|
|ROS||Reactive oxygen species|
|CHOP||CCAAT/enhancer-binding protein homologous protein|
|NF-κB||Nuclear transcription factor-kappa B|
|OSCC||Oral squamous cell carcinoma|
|TLR4||Toll-like receptor 4|
|iNOS||Inducible nitric oxide synthase|
|TNF-α||Tumor necrosis factor-α|
|TRPA1||Transient receptor potential ankyrin 1|
|TNBS||Trinitrobenzene sulfonic acid|
|MDS||Macroscopic damage score|
|DSS||Dextran sulphate sodium|
|CGRP||Calcitonin gene-related peptide|
- Bevan, S.; Hothi, S.; Hughes, G.; James, I.F.; Rang, H.P.; Shah, K.; Walpole, C.S.; Yeats, J.C. Capsazepine: A competitive antagonist of the sensory neurone excitant capsaicin. Br. J. Pharm. 1992, 107, 544–552. [Google Scholar] [CrossRef]
- Rollyson, W.D.; Stover, C.A.; Brown, K.C.; Perry, H.E.; Stevenson, C.D.; McNees, C.A.; Ball, J.G.; Valentovic, M.A.; Dasgupta, P. Bioavailability of capsaicin and its implications for drug delivery. J. Control. Release Off. J. Control. Release Soc. 2014, 196, 96–105. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Hellmich, U.A.; Gaudet, R. Structural biology of TRP channels. Handb. Exp. Pharm. 2014, 223, 963–990. [Google Scholar]
- Huang, J.K.; Cheng, H.H.; Huang, C.J.; Kuo, C.C.; Chen, W.C.; Liu, S.I.; Hsu, S.S.; Chang, H.T.; Lu, Y.C.; Tseng, L.L.; et al. Effect of capsazepine on cytosolic Ca(2+) levels and proliferation of human prostate cancer cells. Toxicol. In Vitro 2006, 20, 567–574. [Google Scholar] [CrossRef]
- Sung, B.; Prasad, S.; Ravindran, J.; Yadav, V.R.; Aggarwal, B.B. Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors. Free Radic Biol. Med. 2012, 53, 1977–1987. [Google Scholar] [CrossRef] [PubMed]
- Chen, C.Y.; Li, W.; Qu, K.P.; Chen, C.R. Piperine exerts anti-seizure effects via the TRPV1 receptor in mice. Eur. J. Pharm. 2013, 714, 288–294. [Google Scholar] [CrossRef]
- Docherty, R.J.; Yeats, J.C.; Piper, A.S. Capsazepine block of voltage-activated calcium channels in adult rat dorsal root ganglion neurones in culture. Br. J. Pharmacol. 1997, 121, 1461–1467. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Liu, L.; Simon, S.A. Capsazepine, a vanilloid receptor antagonist, inhibits nicotinic acetylcholine receptors in rat trigeminal ganglia. Neurosci. Lett. 1997, 228, 29–32. [Google Scholar] [CrossRef]
- Zuo, G.F.; Li, M.H.; Zhang, J.X.; Li, B.; Wang, Z.M.; Wang, Q.; Xiao, H.; Chen, S.L. Capsazepine concentration dependently inhibits currents in HEK 293 cells mediated by human hyperpolarization-activated cyclic nucleotide-gated 2 and 4 channels. Exp. Biol. Med. 2013, 238, 1055–1061. [Google Scholar] [CrossRef]
- Deorukhkar, A.; Krishnan, S.; Sethi, G.; Aggarwal, B.B. Back to basics: How natural products can provide the basis for new therapeutics. Expert Opin. Investig. Drugs 2007, 16, 1753–1773. [Google Scholar] [CrossRef]
- Yang, S.F.; Weng, C.J.; Sethi, G.; Hu, D.N. Natural bioactives and phytochemicals serve in cancer treatment and prevention. Evid Based Complement. Altern. Med. 2013, 2013, 698190. [Google Scholar] [CrossRef]
- Tang, C.H.; Sethi, G.; Kuo, P.L. Novel medicines and strategies in cancer treatment and prevention. Biomed. Res. Int. 2014, 2014, 474078. [Google Scholar] [CrossRef]
- Hsieh, Y.S.; Yang, S.F.; Sethi, G.; Hu, D.N. Natural bioactives in cancer treatment and prevention. Biomed. Res. Int. 2015, 2015, 182835. [Google Scholar] [CrossRef]
- Yarla, N.S.; Bishayee, A.; Sethi, G.; Reddanna, P.; Kalle, A.M.; Dhananjaya, B.L.; Dowluru, K.S.; Chintala, R.; Duddukuri, G.R. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin. Cancer Biol. 2016, 40–41, 48–81. [Google Scholar] [CrossRef]
- Hasanpourghadi, M.; Looi, C.Y.; Pandurangan, A.K.; Sethi, G.; Wong, W.F.; Mustafa, M.R. Phytometabolites Targeting the Warburg Effect in Cancer Cells: A Mechanistic Review. Curr. Drug Targets 2017, 18, 1086–1094. [Google Scholar] [CrossRef]
- Shanmugam, M.K.; Warrier, S.; Kumar, A.P.; Sethi, G.; Arfuso, F. Potential Role of Natural Compounds as Anti-Angiogenic Agents in Cancer. Curr. Vasc. Pharm. 2017, 15, 503–519. [Google Scholar] [CrossRef]
- Shanmugam, M.K.; Kannaiyan, R.; Sethi, G. Targeting cell signaling and apoptotic pathways by dietary agents: Role in the prevention and treatment of cancer. Nutr. Cancer 2011, 63, 161–173. [Google Scholar] [CrossRef]
- Aggarwal, B.B.; Sethi, G.; Baladandayuthapani, V.; Krishnan, S.; Shishodia, S. Targeting cell signaling pathways for drug discovery: An old lock needs a new key. J. Cell Biochem. 2007, 102, 580–592. [Google Scholar] [CrossRef]
- Shanmugam, M.K.; Nguyen, A.H.; Kumar, A.P.; Tan, B.K.; Sethi, G. Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer. Cancer Lett. 2012, 320, 158–170. [Google Scholar] [CrossRef][Green Version]
- Shanmugam, M.K.; Lee, J.H.; Chai, E.Z.; Kanchi, M.M.; Kar, S.; Arfuso, F.; Dharmarajan, A.; Kumar, A.P.; Ramar, P.S.; Looi, C.Y.; et al. Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds. Semin. Cancer Biol. 2016, 40–41, 35–47. [Google Scholar] [CrossRef]
- Bishayee, A.; Sethi, G. Bioactive natural products in cancer prevention and therapy: Progress and promise. Semin. Cancer Biol. 2016, 40–41, 1–3. [Google Scholar] [CrossRef] [PubMed]
- Tewari, D.; Nabavi, S.F.; Nabavi, S.M.; Sureda, A.; Farooqi, A.A.; Atanasov, A.G.; Vacca, R.A.; Sethi, G.; Bishayee, A. Targeting activator protein 1 signaling pathway by bioactive natural agents: Possible therapeutic strategy for cancer prevention and intervention. Pharm. Res. 2018, 128, 366–375. [Google Scholar] [CrossRef] [PubMed]
- Ko, J.H.; Sethi, G.; Um, J.Y.; Shanmugam, M.K.; Arfuso, F.; Kumar, A.P.; Bishayee, A.; Ahn, K.S. The Role of Resveratrol in Cancer Therapy. Int. J. Mol. Sci. 2017, 18, 2589. [Google Scholar] [CrossRef] [PubMed]
- Jung, Y.Y.; Hwang, S.T.; Sethi, G.; Fan, L.; Arfuso, F.; Ahn, K.S. Potential Anti-Inflammatory and Anti-Cancer Properties of Farnesol. Molecules 2018, 23, 2827. [Google Scholar] [CrossRef] [PubMed]
- Merarchi, M.; Sethi, G.; Fan, L.; Mishra, S.; Arfuso, F.; Ahn, K.S. Molecular Targets Modulated by Fangchinoline in Tumor Cells and Preclinical Models. Molecules 2018, 23, 2538. [Google Scholar] [CrossRef]
- Sethi, G.; Shanmugam, M.K.; Warrier, S.; Merarchi, M.; Arfuso, F.; Kumar, A.P.; Bishayee, A. Pro-Apoptotic and Anti-Cancer Properties of Diosgenin: A Comprehensive and Critical Review. Nutrients 2018, 10, 645. [Google Scholar] [CrossRef]
- Lee, J.H.; Kim, C.; Baek, S.H.; Ko, J.H.; Lee, S.G.; Yang, W.M.; Um, J.Y.; Sethi, G.; Ahn, K.S. Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer. Oncotarget 2017, 8, 17700–17711. [Google Scholar] [CrossRef]
- Fazzari, J.; Balenko, M.D.; Zacal, N.; Singh, G. Identification of capsazepine as a novel inhibitor of system xc(−) and cancer-induced bone pain. J. Pain Res. 2017, 10, 915–925. [Google Scholar] [CrossRef]
- Gonzales, C.B.; Kirma, N.B.; De La Chapa, J.J.; Chen, R.; Henry, M.A.; Luo, S.; Hargreaves, K.M. Vanilloids induce oral cancer apoptosis independent of TRPV1. Oral Oncol. 2014, 50, 437–447. [Google Scholar] [CrossRef][Green Version]
- Teng, H.P.; Huang, C.J.; Yeh, J.H.; Hsu, S.S.; Lo, Y.K.; Cheng, J.S.; Cheng, H.H.; Chen, J.S.; Jiann, B.P.; Chang, H.T.; et al. Capsazepine elevates intracellular Ca2+ in human osteosarcoma cells, questioning its selectivity as a vanilloid receptor antagonist. Life Sci. 2004, 75, 2515–2526. [Google Scholar] [CrossRef]
- Chai, E.Z.; Shanmugam, M.K.; Arfuso, F.; Dharmarajan, A.; Wang, C.; Kumar, A.P.; Samy, R.P.; Lim, L.H.; Wang, L.; Goh, B.C.; et al. Targeting transcription factor STAT3 for cancer prevention and therapy. Pharm. Ther. 2016, 162, 86–97. [Google Scholar] [CrossRef]
- Arora, L.; Kumar, A.P.; Arfuso, F.; Chng, W.J.; Sethi, G. The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies. Cancers 2018, 10, 327. [Google Scholar] [CrossRef]
- Lee, J.H.; Kim, C.; Lee, S.G.; Sethi, G.; Ahn, K.S. Ophiopogonin D, a Steroidal Glycoside Abrogates STAT3 Signaling Cascade and Exhibits Anti-Cancer Activity by Causing GSH/GSSG Imbalance in Lung Carcinoma. Cancers 2018, 10, 427. [Google Scholar] [CrossRef]
- Wong, A.L.A.; Hirpara, J.L.; Pervaiz, S.; Eu, J.Q.; Sethi, G.; Goh, B.C. Do STAT3 inhibitors have potential in the future for cancer therapy? Expert Opin. Investig. Drugs 2017, 26, 883–887. [Google Scholar] [CrossRef]
- Zhang, J.; Ahn, K.S.; Kim, C.; Shanmugam, M.K.; Siveen, K.S.; Arfuso, F.; Samym, R.P.; Deivasigamanim, A.; Lim, L.H.; Wang, L.; et al. Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model. Antioxid. Redox Signal. 2016, 24, 575–589. [Google Scholar] [CrossRef]
- Subramaniam, A.; Shanmugam, M.K.; Ong, T.H.; Li, F.; Perumal, E.; Chen, L.; Vali, S.; Abbasi, T.; Kapoor, S.; Ahn, K.S.; et al. Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3. Br. J. Pharm. 2013, 170, 807–821. [Google Scholar] [CrossRef][Green Version]
- Subramaniam, A.; Shanmugam, M.K.; Perumal, E.; Li, F.; Nachiyappan, A.; Dai, X.; Swamy, S.N.; Ahn, K.S.; Kumar, A.P.; Tan, B.K.; et al. Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim. Biophys. Acta 2013, 1835, 46–60. [Google Scholar] [CrossRef][Green Version]
- Kim, C.; Lee, S.G.; Yang, W.M.; Arfuso, F.; Um, J.Y.; Kumar, A.P.; Bian, J.; Sethi, G.; Ahn, K.S. Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model. Cancer Lett. 2018, 431, 123–141. [Google Scholar] [CrossRef]
- Jung, Y.Y.; Lee, J.H.; Nam, D.; Narula, A.S.; Namjoshi, O.A.; Blough, B.E.; Um, J.Y.; Sethi, G.; Ahn, K.S. Anti-myeloma Effects of Icariin Are Mediated Through the Attenuation of JAK/STAT3-Dependent Signaling Cascade. Front. Pharmacol. 2018, 9, 531. [Google Scholar] [CrossRef]
- Siveen, K.S.; Sikka, S.; Surana, R.; Dai, X.; Zhang, J.; Kumar, A.P.; Tan, B.K.; Sethi, G.; Bishayee, A. Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim. Biophys. Acta 2014, 1845, 136–154. [Google Scholar] [CrossRef][Green Version]
- Prasad, S.; Kim, J.H.; Gupta, S.C.; Aggarwal, B.B. Targeting death receptors for TRAIL by agents designed by Mother Nature. Trends Pharmacol. Sci. 2014, 35, 520–536. [Google Scholar] [CrossRef] [PubMed]
- Dai, X.; Zhang, J.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Kumar, A.P.; Ahn, K.S.; Sethi, G. Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exp. Biol. Med. 2015, 240, 760–773. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Subramaniam, A.; Loo, S.Y.; Rajendran, P.; Manu, K.A.; Perumal, E.; Li, F.; Shanmugam, M.K.; Siveen, K.S.; Park, J.I.; Ahn, K.S.; et al. An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins. Apoptosis Int. J. Program. Cell Death 2013, 18, 1175–1187. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Kamat, A.M.; Sethi, G.; Aggarwal, B.B. Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-kappaB and nuclear factor-kappaB-regulated gene products in IFN-alpha-sensitive and IFN-alpha-resistant human bladder cancer cells. Mol. Cancer Ther. 2007, 6, 1022–1030. [Google Scholar] [CrossRef] [PubMed]
- Yamaguchi, H.; Wang, H.G. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem. 2004, 279, 45495–45502. [Google Scholar] [CrossRef] [PubMed]
- Yoshida, T.; Shiraishi, T.; Nakata, S.; Horinaka, M.; Wakada, M.; Mizutani, Y.; Miki, T.; Sakai, T. Proteasome inhibitor MG132 induces death receptor 5 through CCAAT/enhancer-binding protein homologous protein. Cancer Res. 2005, 65, 5662–5667. [Google Scholar] [CrossRef]
- Dai, X.; Wang, L.; Deivasigamni, A.; Looi, C.Y.; Karthikeyan, C.; Trivedi, P.; Chinnathambi, A.; Alharbi, S.A.; Arfuso, F.; Dharmarajan, A.; et al. A novel benzimidazole derivative, MBIC inhibits tumor growth and promotes apoptosis via activation of ROS-dependent JNK signaling pathway in hepatocellular carcinoma. Oncotarget 2017, 8, 12831–12842. [Google Scholar] [CrossRef][Green Version]
- Prasad, S.; Gupta, S.C.; Tyagi, A.K. Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett. 2017, 387, 95–105. [Google Scholar] [CrossRef]
- Kim, S.M.; Kim, C.; Bae, H.; Lee, J.H.; Baek, S.H.; Nam, D.; Chung, W.S.; Shim, B.S.; Lee, S.G.; Kim, S.H.; et al. 6-Shogaol exerts anti-proliferative and pro-apoptotic effects through the modulation of STAT3 and MAPKs signaling pathways. Mol. Carcinog. 2015, 54, 1132–1146. [Google Scholar] [CrossRef]
- Woo, C.C.; Hsu, A.; Kumar, A.P.; Sethi, G.; Tan, K.H. Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: The role of p38 MAPK and ROS. PLoS ONE 2013, 8, e75356. [Google Scholar] [CrossRef]
- Gupta, S.C.; Hevia, D.; Patchva, S.; Park, B.; Koh, W.; Aggarwal, B.B. Upsides and downsides of reactive oxygen species for cancer: The roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid. Redox Signal. 2012, 16, 1295–1322. [Google Scholar] [CrossRef]
- Park, K.R.; Nam, D.; Yun, H.M.; Lee, S.G.; Jang, H.J.; Sethi, G.; Cho, S.K.; Ahn, K.S. beta-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett. 2011, 312, 178–188. [Google Scholar] [CrossRef] [PubMed]
- de Sa Junior, P.L.; Camara, D.A.D.; Porcacchia, A.S.; Fonseca, P.M.M.; Jorge, S.D.; Araldi, R.P.; Ferreira, A.K. The Roles of ROS in Cancer Heterogeneity and Therapy. Oxid. Med. Cell. Longev. 2017, 2017, 2467940. [Google Scholar] [CrossRef]
- Sanchez, A.M.; Sanchez, M.G.; Malagarie-Cazenave, S.; Olea, N.; Diaz-Laviada, I. Induction of apoptosis in prostate tumor PC-3 cells and inhibition of xenograft prostate tumor growth by the vanilloid capsaicin. Apoptosis Int. J. Program. Cell Death 2006, 11, 89–99. [Google Scholar] [CrossRef] [PubMed]
- Ziglioli, F.; Frattini, A.; Maestroni, U.; Dinale, F.; Ciufifeda, M.; Cortellini, P. Vanilloid-mediated apoptosis in prostate cancer cells through a TRPV-1 dependent and a TRPV-1-independent mechanism. Acta Bio-Med. Atenei Parm. 2009, 80, 13–20. [Google Scholar]
- Li, F.; Zhang, J.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Kumar, A.P.; Ahn, K.S.; Sethi, G. NF-kappaB in cancer therapy. Arch. Toxicol. 2015, 89, 711–731. [Google Scholar] [CrossRef] [PubMed]
- Manu, K.A.; Shanmugam, M.K.; Ramachandran, L.; Li, F.; Fong, C.W.; Kumar, A.P.; Tan, P.; Sethi, G. First evidence that gamma-tocotrienol inhibits the growth of human gastric cancer and chemosensitizes it to capecitabine in a xenograft mouse model through the modulation of NF-kappaB pathway. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2012, 18, 2220–2229. [Google Scholar] [CrossRef] [PubMed]
- Sethi, G.; Shanmugam, M.K.; Ramachandran, L.; Kumar, A.P.; Tergaonkar, V. Multifaceted link between cancer and inflammation. Biosci. Rep. 2012, 32, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Li, F.; Sethi, G. Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. Biochim. Biophys. Acta 2010, 1805, 167–180. [Google Scholar]
- Sethi, G.; Tergaonkar, V. Potential pharmacological control of the NF-kappaB pathway. Trends Pharmacol. Sci. 2009, 30, 313–321. [Google Scholar] [CrossRef]
- Ahn, K.S.; Sethi, G.; Aggarwal, B.B. Nuclear factor-kappa B: From clone to clinic. Curr. Mol. Med. 2007, 7, 619–637. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Ahn, K.S.; Shanmugam, M.K.; Wang, H.; Shen, H.; Arfuso, F.; Chinnathambi, A.; Alharbi, S.A.; Chang, Y.; Sethi, G.; et al. Oleuropein induces apoptosis via abrogating NF-kappaB activation cascade in estrogen receptor-negative breast cancer cells. J. Cell. Biochem. 2018. [Google Scholar] [CrossRef]
- Puar, Y.R.; Shanmugam, M.K.; Fan, L.; Arfuso, F.; Sethi, G.; Tergaonkar, V. Evidence for the Involvement of the Master Transcription Factor NF-kappaB in Cancer Initiation and Progression. Biomedicines 2018, 6, 82. [Google Scholar] [CrossRef] [PubMed]
- Chai, E.Z.; Siveen, K.S.; Shanmugam, M.K.; Arfuso, F.; Sethi, G. Analysis of the intricate relationship between chronic inflammation and cancer. Biochem. J. 2015, 468, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Shanmugam, M.K.; Ahn, K.S.; Lee, J.H.; Kannaiyan, R.; Mustafa, N.; Manu, K.A.; Siveen, K.S.; Sethi, G.; Chng, W.J.; Kumar, A.P. Celastrol Attenuates the Invasion and Migration and Augments the Anticancer Effects of Bortezomib in a Xenograft Mouse Model of Multiple Myeloma. Front. Pharmacol. 2018, 9, 365. [Google Scholar] [CrossRef] [PubMed]
- Manu, K.A.; Shanmugam, M.K.; Ramachandran, L.; Li, F.; Siveen, K.S.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Arfuso, F.; Kumar, A.P.; et al. Isorhamnetin augments the anti-tumor effect of capeciatbine through the negative regulation of NF-kappaB signaling cascade in gastric cancer. Cancer Lett. 2015, 363, 28–36. [Google Scholar] [CrossRef]
- Li, F.; Shanmugam, M.K.; Siveen, K.S.; Wang, F.; Ong, T.H.; Loo, S.Y.; Swamy, M.M.; Mandal, S.; Kumar, A.P.; Goh, B.C.; et al. Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers. Oncotarget 2015, 6, 5147–5163. [Google Scholar] [CrossRef][Green Version]
- Han, S.; Lee, J.H.; Kim, C.; Nam, D.; Chung, W.S.; Lee, S.G.; Ahn, K.S.; Cho, S.K.; Cho, M.; Ahn, K.S. Capillarisin inhibits iNOS, COX-2 expression, and proinflammatory cytokines in LPS-induced RAW 264.7 macrophages via the suppression of ERK, JNK, and NF-kappaB activation. Immunopharmacol. Immunotoxicol. 2013, 35, 34–42. [Google Scholar] [CrossRef]
- Kasckow, J.W.; Mulchahey, J.J.; Geracioti, T.D., Jr. Effects of the vanilloid agonist olvanil and antagonist capsazepine on rat behaviors. Prog. Neuropsychopharmacol. Biol. Psychiatry 2004, 28, 291–295. [Google Scholar] [CrossRef]
- Oh, G.S.; Pae, H.O.; Seo, W.G.; Kim, N.Y.; Pyun, K.H.; Kim, I.K.; Shin, M.; Chung, H.T. Capsazepine, a vanilloid receptor antagonist, inhibits the expression of inducible nitric oxide synthase gene in lipopolysaccharide-stimulated RAW264.7 macrophages through the inactivation of nuclear transcription factor-kappa B. Int. Immunopharmacol. 2001, 1, 777–784. [Google Scholar] [CrossRef]
- Phillips, E.; Reeve, A.; Bevan, S.; McIntyre, P. Identification of species-specific determinants of the action of the antagonist capsazepine and the agonist PPAHV on TRPV1. J. Biol. Chem. 2004, 279, 17165–17172. [Google Scholar] [CrossRef] [PubMed]
- Walker, K.M.; Urban, L.; Medhurst, S.J.; Patel, S.; Panesar, M.; Fox, A.J.; McIntyre, P. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J. Pharmacol. Exp. Ther. 2003, 304, 56–62. [Google Scholar] [CrossRef] [PubMed]
- Kistner, K.; Siklosi, N.; Babes, A.; Khalil, M.; Selescu, T.; Zimmermann, K.; Wirtz, S.; Becker, C.; Neurath, M.F.; Reeh, P.W.; et al. Systemic desensitization through TRPA1 channels by capsazepine and mustard oil—A novel strategy against inflammation and pain. Sci. Rep. 2016, 6, 28621. [Google Scholar] [CrossRef]
- Fujino, K.; Takami, Y.; de la Fuente, S.G.; Ludwig, K.A.; Mantyh, C.R. Inhibition of the vanilloid receptor subtype-1 attenuates TNBS-colitis. J. Gastrointest. Surg. 2004, 8, 842–847; discussion 847–848. [Google Scholar] [CrossRef] [PubMed]
- Kihara, N.; de la Fuente, S.G.; Fujino, K.; Takahashi, T.; Pappas, T.N.; Mantyh, C.R. Vanilloid receptor-1 containing primary sensory neurones mediate dextran sulphate sodium induced colitis in rats. Gut 2003, 52, 713–719. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Vigna, S.R.; Shahid, R.A.; Nathan, J.D.; McVey, D.C.; Liddle, R.A. Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced pancreatitis in rats. Pancreas 2011, 40, 708–714. [Google Scholar] [CrossRef]
- White, N.J.; Pukrittayakamee, S.; Hien, T.T.; Faiz, M.A.; Mokuolu, O.A.; Dondorp, A.M. Malaria. Lancet 2014, 383, 723–735. [Google Scholar] [CrossRef]
- Cho, S.J.; Vaca, M.A.; Miranda, C.J.; N’Gouemo, P. Inhibition of transient potential receptor vanilloid type 1 suppresses seizure susceptibility in the genetically epilepsy-prone rat. CNS Neurosci. Ther. 2018, 24, 18–28. [Google Scholar] [CrossRef]
- Nguyen, T.L.; Nam, Y.S.; Lee, S.Y.; Kim, H.C.; Jang, C.G. Effects of capsazepine, a transient receptor potential vanilloid type 1 antagonist, on morphine-induced antinociception, tolerance, and dependence in mice. Br. J. Anaesth. 2010, 105, 668–674. [Google Scholar] [CrossRef][Green Version]
- Gonzalez-Reyes, L.E.; Ladas, T.P.; Chiang, C.C.; Durand, D.M. TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo. Exp. Neurol. 2013, 250, 321–332. [Google Scholar] [CrossRef][Green Version]
- Wick, E.C.; Hoge, S.G.; Grahn, S.W.; Kim, E.; Divino, L.A.; Grady, E.F.; Bunnett, N.W.; Kirkwood, K.S. Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2006, 290, G959–G969. [Google Scholar] [CrossRef][Green Version]
- Fernandes, E.S.; Brito, C.X.; Teixeira, S.A.; Barboza, R.; dos Reis, A.S.; Azevedo-Santos, A.P.; Muscara, M.; Costa, S.K.; Marinho, C.R.; Brain, S.D.; et al. TRPV1 antagonism by capsazepine modulates innate immune response in mice infected with Plasmodium berghei ANKA. Mediat. Inflamm. 2014, 2014, 506450. [Google Scholar] [CrossRef]
- Ghazizadeh, V.; Naziroglu, M. Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats. Metab. Brain Dis. 2014, 29, 787–799. [Google Scholar] [CrossRef]
- Naziroglu, M.; Ozkan, F.F.; Hapil, S.R.; Ghazizadeh, V.; Cig, B. Epilepsy but not mobile phone frequency (900 MHz) induces apoptosis and calcium entry in hippocampus of epileptic rat: Involvement of TRPV1 channels. J. Membr. Biol. 2015, 248, 83–91. [Google Scholar] [CrossRef]
- Shirazi, M.; Izadi, M.; Amin, M.; Rezvani, M.E.; Roohbakhsh, A.; Shamsizadeh, A. Involvement of central TRPV1 receptors in pentylenetetrazole and amygdala-induced kindling in male rats. Neurol. Sci. 2014, 35, 1235–1241. [Google Scholar] [CrossRef]
- Manna, S.S.; Umathe, S.N. A possible participation of transient receptor potential vanilloid type 1 channels in the antidepressant effect of fluoxetine. Eur. J. Pharm. 2012, 685, 81–90. [Google Scholar] [CrossRef]
- Naziroglu, M.; Ovey, I.S. Involvement of apoptosis and calcium accumulation through TRPV1 channels in neurobiology of epilepsy. Neuroscience 2015, 293, 55–66. [Google Scholar] [CrossRef]
- Santos, C.J.; Stern, C.A.; Bertoglio, L.J. Attenuation of anxiety-related behaviour after the antagonism of transient receptor potential vanilloid type 1 channels in the rat ventral hippocampus. Behav. Pharm. 2008, 19, 357–360. [Google Scholar] [CrossRef]
- Trevisani, M.; Patacchini, R.; Nicoletti, P.; Gatti, R.; Gazzieri, D.; Lissi, N.; Zagli, G.; Creminon, C.; Geppetti, P.; Harrison, S. Hydrogen sulfide causes vanilloid receptor 1-mediated neurogenic inflammation in the airways. Br. J. Pharmacol. 2005, 145, 1123–1131. [Google Scholar] [CrossRef][Green Version]
- Bhatia, M.; Zhi, L.; Zhang, H.; Ng, S.W.; Moore, P.K. Role of substance P in hydrogen sulfide-induced pulmonary inflammation in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 2006, 291, L896–L904. [Google Scholar] [CrossRef]
- Lin, Q.; Li, D.; Xu, X.; Zou, X.; Fang, L. Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin. Mol. Pain 2007, 3, 30. [Google Scholar] [CrossRef] [PubMed]
- Flores, C.M.; Leong, A.S.; Dussor, G.O.; Harding-Rose, C.; Hargreaves, K.M.; Kilo, S. Capsaicin-evoked CGRP release from rat buccal mucosa: Development of a model system for studying trigeminal mechanisms of neurogenic inflammation. Eur. J. Neurosci. 2001, 14, 1113–1120. [Google Scholar] [CrossRef] [PubMed]
- Ang, S.F.; Moochhala, S.M.; Bhatia, M. Hydrogen sulfide promotes transient receptor potential vanilloid 1-mediated neurogenic inflammation in polymicrobial sepsis. Crit. Care Med. 2010, 38, 619–628. [Google Scholar] [CrossRef]
- Ang, S.F.; Moochhala, S.M.; MacAry, P.A.; Bhatia, M. Hydrogen sulfide and neurogenic inflammation in polymicrobial sepsis: Involvement of substance P and ERK-NF-kappaB signaling. PLoS ONE 2011, 6, e24535. [Google Scholar] [CrossRef] [PubMed]
Figure 1. The chemical structures of capsaicin and capsazepine.
Figure 2. Pharmacological properties of capsazepine.
Figure 3. Potential mechanisms underlying reported anti-cancer effects of capsazepine.
Figure 4. Potential mechanisms regulating anti-inflammatory effects of capsazepine.
Table 1. Anti-cancer effects of capsazepine in vitro.
|Origin||Cell Lines||Concentrations||Molecular Targets||Mechanism of Actions||Ref.|
|Prostate||DU145||1, 2.5, 5 μM for 6, 24 h||STAT3, JAK↓||Apoptosis↑|||
|PC-3||200 μM from for 5 h||Intracellular |
|Breast||MDA-MB-231||25 μM for 48 h||System xc− (xCT), cystine||ROS↑ |
|Colon||HCT166||10, 30 μM for 6, 24 h||ROS, JNK, CHOP||Apoptosis↑|||
|Oral||SCC4||30, 60, 90 μM for 24 h||ROS||cell proliferation↓ |
|Bone||MG63||50, 100, 150, 200 μM for 4 h||Intracellular |
|Tumor cell multiplication↓|||
Table 2. Anti-cancer effects of Capsazepine on animal studies.
|Prostate cancer||mice||1, 5 mg/kg/day for 20 days||Tumor growth↓||.|
|Breast cancer||mice||10, 5 mg/kg/day for 36 days||CIBP-induced nociceptive behaviors|||
|Oral cancer||mice||0.02, 0.04 mg/day for 12, 16 and 18 days||Tumor growth↓|||
Table 3. Anti-inflammatory Effects of capsazepine in vitro.
|Origin||Cell Lines||Concentrations||Molecular Targets||Mechanism of Actions||Ref.|
|Macrophage||RAW264.7||1, 5, 10 μM for 6 h||NF-κB||Immune response↑|||
|Kidney||HEK293t||10 μM for 10 s||TRPA1||Inflammation↓|||
|Hippocampus||Hippocampal ca1 pyramidal cells||10, 100 μM for 20 min||TRPV1||Apoptosis↑, cell proliferation↓|||
Table 4. Anti-inflammatory effects of capsazepine in preclinical disease models.
|Colitis||Rat||37.7 × 10−5 mg/kg/day for 6 days||Inflammatory parameter↓|||
|Rat||0.1 mg/kg/day for 6 days||DAI, MPO activity↓|||
|Rat||1 mg/kg/day for 7 days||Inflammatory parameter↓|||
|Pancreatitis||Rat||37.7 × 10−3 mg/kg for 30 min before surgery||Inflammatory parameter↓|||
|Malaria||mice||0.05 mg/kg/day for 6 days||Immune response↑|||
|Epilepsy||rat||1, 3, 10 mg/kg/day for 7 days||seizure severity↓|||
|mice||5 mg/kg/test||antinociceptive effects|||
|mice||50 mg/kg||4-AP(4-aminopyridine)-induced epileptic status activity↓|||
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).