There is persuasive epidemiological and experimental evidence that dietary phytochemicals have anticancer activity. Capsaicin is a bioactive phytochemical abundant in red and chili peppers. Capsaicin has been shown to alter the expression of several genes involved in cancer cell survival, growth arrest, angiogenesis and metastasis. Recently, many research groups, including ours, found that capsaicin targets multiple signaling pathways, oncogenes and tumor-suppressor genes in various types of cancer models. In this review article, we highlight multiple molecular targets responsible for the anticancer mechanism of capsaicin.
Search for terms x. Footnotes Competing interests: Dr. Tumor volumes were measured daily. Nubiles net traci size image. BSG and AB designed and performed experiments. Free Radic Res 38 : - Cell viability by MTT is shown on the right. For treatment Capsaicn, cells were plated and grown over night, the medium was then replaced with serum-free RPMI for 4 hours and then incubated with different doses of capsaicin for the indicated times. Pain Med. Int J Oncol.
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Fulda S, Kogel D. I'm currently searching for scientifically documented success stories, I'll post my findings Regulation of autophagy by ROS: physiology and pathology. It has been previously Capsaicin a cure for prostate cancer that capsaicin inhibits prostate cell proliferation with different potency in the different cell lines. After 2 doses of bicalutamide, the patient discontinued the bicalutamide due to adverse reactions including lightheadedness, hallucinations and pre-syncope, events which caused him to present to the emergency room. Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy. By detecting how the molecule interacts with cell membranes, they hope to find better ways of delivering it when attempting to Harassment preventing supervisor hand sexual cancer cells. The present manuscript examines the ability of capsaicin to trigger autophagy in prostate cancer androgen-sensitive and androgen-independent cells and Czpsaicin role of autophagy in Capsaiciin cytotoxicity. Related Posts. Tennessee farmer converts giant prostafe into kayak.
Capsaicin is the main pungent component of chili peppers.
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- Capsaicin, the pungent ingredient of red hot chili peepers, has been shown to have anti-cancer activities in several cancer cells, including prostate cancer.
- Capsaicin is the main pungent component of chili peppers.
Capsaicin, the pungent ingredient of red hot chili peepers, has been shown to have anti-cancer activities in several cancer cells, including prostate cancer. However, the precise mechanisms by which capsaicin exerts its anti-proliferative effect in prostate cancer cells remain questionable. Herein, we have tested the involvement of autophagy on the capsaicin mechanism of action on prostate cancer LNCaP and PC-3 cells.
Co-treatment of cells with NAC and capsaicin abrogated the effects of capsaicin on autophagy and cell death. Prostate cancer PC is the second highest cause of cancer-related death among men in developed countries [ 1 ].
In spite of this, cancer deaths predicted for the next years are undesirably high and a substantial portion of cancer cases and deaths could be prevented by broadly applying effective therapies. Unfortunately, the appearance of hormone refractory cancer cells leads eventually to the recurrence of cancer which turns to a castration resistant prostate cancer CRPC for which the only treatment option is chemotherapy with docetaxel.
Unfortunately, patients treated with docetaxel experience significant toxicity and sometimes resistance and inevitably decline to disease progression. Therefore, a great effort is required to improve treatment options and effectiveness. An emerging area of cancer research is focused on chemoprevention by natural compounds.
Dietary products are of particular interest as chemo-preventive and chemo-therapeutic agents because of their low toxicity and potent efficacy. One of the food additive consumed worldwide is the pungent compound capsaicin which is considered a promising nutraceutical in anticancer therapy [ 6 ]. Capsaicin 8-methyl-N-vanillylnoneamide is the major ingredient of the hot chili peppers belonging to the genus Capsicum and responsible for their spicy flavor and burning sensation.
Accumulating data have demonstrated the anti-neoplastic activity of capsaicin in many cancer cell lines as well as in vivo [ 7 ]. In particular capsaicin has shown anti-tumor properties against prostate cancer, inhibiting prostate tumor cells growth in vitro and reducing prostate growth in animal models [ 8 , 9 ]. Several convergent studies have revealed that capsaicin caused cell cycle arrest and trigger apoptosis in human prostate carcinoma cells [ 10 , 11 ].
In this line, we have previously shown that in prostate PC-3 cancer cells, capsaicin induces ROS generation which triggers endoplasmic reticulum stress that precedes apoptosis [ 12 ]. Endoplasmic reticulum stress accelerates the degradation of accumulated proteins within the lumen and may induce programmed cell death through activation of autophagy.
Autophagy, or cellular self-digestion, is a homeostatic process where cytosolic components are targeted for removal or turnover in membrane-bound compartments autophagosomes that fuse with the lysosome forming the autophagolysosome. This cellular pathway is crucial for cellular fitness prolonging cell survival by recycling nutrients and energy.
However, under stressful conditions sustained autophagy activation can promote cell death. Autophagy dysfunction is often associated with many diseases, including cancer, either promoting pro-survival and pro-death mechanisms depending upon the tumor type, genetic context and cellular conditions and thus, the implication of autophagy in cancer is still not completely understood.
Particularly in prostate cancer, evidence of dysregulation of autophagy related proteins provide evidence that autophagy plays a relevant role in both disease progression and therapeutic resistance [ 13 ]. Therefore, targeting programmed cell death through modulation of autophagy has become a promising approach to fighting prostate cancer [ 14 , 15 ]. In fact, it has been carried out autophagy-oriented clinical trials that involve autophagy modulation with therapeutic benefits [ 16 ].
In addition, natural compounds have revealed as promising agents able to modulate autophagy in prostate cancer [ 17 ]. The present manuscript examines the ability of capsaicin to trigger autophagy in prostate cancer androgen-sensitive and androgen-independent cells and the role of autophagy in capsaicin-induced cytotoxicity. A link between capsaicin-induced autophagy and ROS production has also been evaluated. We then studied the time- and dose-dependent effect of capsaicin on prostate cancer cell lines viability.
Porstate cancer cells were treated with different doses of capsaicin for 24, 48 and 72 hours. Cell viability was monintored by MTT.
Akt kinase mediates a potent anti-apoptotic signal in prostatic cancer and inhibition of this pathway has become an attractive mechanism to increase the efficacy of traditional chemotherapies. When active, mTORC1 triggers cell growth and proliferation by promoting protein synthesis, lipid biogenesis, metabolism and reducing autophagy. To investigate whether capsaicin impact this signaling pathway we determined the levels of phosphorylated Akt at Ser which is a hallmark of Akt activation.
When prostate cells were incubated with capsaicin there was a time- and dose-dependent decrease in Akt phosphorylation pointing to an inhibition of this signaling pathway. Lower panel, densitometric values of the blots. So, we then tested whether capsaicin induced autophagy in the prostate cancer cell lines. During autophagy, microtubule-associated protein 1 light chain 3 LC3 is cleaved at its C-terminal arginine residue to form LC3-I.
This can be measured by observing the shift in molecular weight on immunoblots. To investigate whether capsaicin induced autophagy in prostate cancer cells, we determined the increase of LC3-II in capsaicin treated cells.
An important point is that autophagy is a dynamic, multi-step process that can be modulated at several steps, both positively and negatively. An increase in LC3-II can reflect either increased autophagosome formation due to augmented autophagic activity, or to reduced turnover of autophagosomes [ 18 ]. To further study the intensity of autophagy activity induced by capsaicin in prostate cells, we measured the levels of the p62 protein which becomes incorporated into the completed autophagosome and is degraded in autolysosomes.
In addition, p62 is also required for the autophagic removal and therefore increased levels of p62 correlates with autophagy inhibition [ 18 ]. Upper panel, a representative image of four experiments. Upper panel and LC3 and p62 proteins were detected by Western blot.
A representative image of three experiments is shown. To corroborate the autophagy blocking we incubated the cells with capsaicin, labelled endogenous LC3 by inmmunofluorescence and incubated cells with Lyso Tracker Red, an acidotropic dye which primarily detect lysosomes.
In addition, capsaicin treatment increased the number of lysosomes. As a further confirmation of this result, we used the protease inhibitors E64 and pepstatin which prevent lysosomal degradation.
LNCaP cells; B. PC-3 cells and C. Image is representative of three experiments. D of three experiments performed in triplicate. To analyze the role of ROS on capsaicin-induced prostate cell death, we incubated the cells with 10 mM NAC prior to the treatment with of capsaicin.
Autophagy related proteins were determined by Western Blot. Image shown is representative of other two experiments. A stronger piece of evidence supporting the idea that NAC suppressed the autophagy blockage induced by capsaicin was obtained by confocal microscopy. To investigate whether autophagy blockage correlated with apoptosis, prostate cells were incubated with capsaicin and levels of the caspase 3 precursor, pro-caspase 3, and poly ADP-ribose polymerase PARP were determined by Western blot.
Likewise, a dose-dependent decrease in PARP levels, which is a marker of apoptosis, was observed in capsaicin-treated cancer cells. Notably, the pre-treatment with NAC not only reduced the accumulation of p62 but also the reduction of pro-caspase 3 and PARP, suggesting a link between autophagy and apoptosis in the prostate cancer cells.
It has been previously described that capsaicin inhibits prostate cell proliferation with different potency in the different cell lines.
Based on these pre-clinical findings, interest in capsaicin is increasing in relation to the management of prostate cancer. As mTOR is one of the main regulators of autophagy we wondered whether capsaicin induced autophagy in prostate cancer cells. Increased LC3 lipidation can reflect induction of autophagy, reduction in autophagosome maturation, or the inability of turnover to degrade the increased amount of autophagosomes formed [ 18 ].
In general, inhibition of autophagy correlates with increased levels of p62, suggesting that steady-state levels of this protein reflect the autophagic status [ 18 ].
Confocal microscopy shows that capsaicin treatment induces an increase in the cytoplasmic LC3 puncta which co-localizes with lysosomes, which are also increased in number. This result suggest that autophagolysosome formation is greater than is its breakdown and therefore they accumulate in the cell. The mechanism through which autophagosomes fuse with lysosomes is not fully understood [ 19 ]. Likewise, 3-MA pretreatment did not have any effect on capsaicin-induced cell death although it has an inhibitory effect when administered alone.
Autophagy is deregulated in various pathological conditions, including cancer. However the final effect of autophagy activation in cancer cells is highly variable depending on the integration of complex signaling pathways and extracellular conditions [ 22 ].
In general, autophagy activation allows cells to respond to stressful environmental conditions such as starvation or hypoxia. This function is particularly important for cancer cells that are characterized by high metabolic demand. As a prosurvival mechanism, autophagy may be used by transformed cells to adapt to the tumor microenvironment characterized by poor oxygen and nutrients supply. By other hand, as a suppressor pathway, autophagy prevents tumor initiation.
Many autophagy regulators have been identified as potential cancer therapeutic agents and some cytotoxic anticancer drugs also induce autophagy [ 22 ]. Previous studies performed by other authors also demonstrate that capsaicin may induce autophagy in several malignant cell lines. Oh et al. The same authors also demonstrated that capsaicin and DHC triggered cell death an autophagy in WI38 normal lung epithelial fibroblast cells [ 24 ].
Studies performed by by Choi et al. Surprisingly, the cytotoxic effect of capsaicin was found to be much higher in normal breast epithelial MCF10A cells than in the malignant cell lines MCF-7 and MDA-MB, although in normal cells capsaicin did not induce autophagy [ 25 ].
Other studies have also shown that capsaicin could induce apoptosis in U glioma cells, and the inhibition of autophagy could contribute to apoptosis [ 27 ]. In our study, the blockage of autophagy induced by capsaicin in prostate cancer cells may contribute to cell death as procaspase 3 and PARP are also activated.
Recent findings have shown an upregulation of autophagy proteins in prostate cancer biopsies which were highly associated with a high Gleason score and to extraprostatic invasion [ 29 ]. Therefore, it seems like in prostate cancer activation of autophagy is necessary to survival of cancer cells. In line with this notion, it has been proposed that the androgen sensitive LNCaP cells can undergo to the autophagic pathway to survive under androgen deprivation conditions, as a mechanism of transition to an androgen-independent state [ 30 ].
Current research also demonstrates that inhibition of the autophagic machinery improves prostate cell killing and tumor responsiveness [ 13 ]. In fact, autophagy inhibition is now being explored in a number of clinical trials for patients with advanced prostate cancer [ 13 ].
Using a cytofluorimetric approach, we have found that capsaicin induces ROS in a time and dose-dependent fashion. ROS can exert different effects according to the basal metabolic rate of the cell. We have previously described that the capsaicin-induced accumulation of ROS in prostate PC-3 cells causes endothelial reticulum stress and triggers apoptosis [ 12 ].
In this study a possible relationship between capsaicin-induced ROS generation and autophagy was examined. Although connections between ROS and autophagy are observed in diverse physiological and pathological conditions, the mode of activation of autophagy and its potential protective role remain incompletely understood [ 32 ].
It is generally accepted that that ROS induce autophagy and autophagy, in turn, serves to reduce oxidative damage. According to our study, we speculate that autophagy is necessary for prostate cell survival and that capsaicin reduces cell proliferation by a mechanism that involves autophagy blocking through ROS generation.
It must be noted that although capsaicin induces an intense ROS increase in the prostate cell line LNCaP, this cell line is less sensitive to the anti-proliferative action of capsaicin as well as to the autophagy blocking. Differences in autophagy induction in both cell lines have been previously found by other authors [ 33 ]. One possible explanation is that autophagy contributes to androgen receptor AR degradation in LNCaP cells [ 34 ] and as capsaicin blocks autophagy, AR may be maintained at levels enough to sustain cell proliferation.
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Capsaicin a cure for prostate cancer. Introduction
Capsaicin may slow PSA doubling time: case report and literature review
Skip to content. According to a team of researchers from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, in collaboration with colleagues from UCLA, the pepper component caused human prostate cancer cells to undergo programmed cell death or apoptosis. Capsaicin induced approximately 80 percent of prostate cancer cells growing in mice to follow the molecular pathways leading to apoptosis.
Prostate cancer tumors treated with capsaicin were about one-fifth the size of tumors in non-treated mice. As described in their study, the scientists observed that capsaicin inhibited the activity of NF-, a molecular mechanism that participates in the pathways leading to apoptosis in many cell types.
Apoptosis is a normal cellular event in many tissues that maintains a balance between newer replacement cells and aged or worn cells. In contrast, cancer cells seek to be immortal and often dodge apoptosis by mutating or deregulating the genes that participate in programmed cell death.
The pepper extract also curbed the growth of prostate cancer cells through regulation of androgen receptors, the steroid activated proteins that control expression of specific growth relating genes. In prostate cancer cells whose growth is dependent on testosterone, the predominant male sex steroid, capsaicin reduced cell proliferation in a dose-dependent manner.
Prostate cancer cells that are androgen independent reacted to capsaicin in a similar manner. Capsaicin reduced the amount of androgen receptor that the tumor cells produced, but did not interfere with normal movement of androgen receptor into the nucleus of the cancer cells where the steroid receptor acts to regulate androgen target genes such as prostate specific antigen PSA.
Capsaicin also interfered with the action of androgen receptors even in cells that were modified to produce excess numbers of androgen receptors. The hot pepper component also reduced cancer cell production of PSA, a protein that often is produced in high quantities by prostate tumors and can signal the presence of prostate cancer in men.
PSA content in the blood of men is used as a diagnostic prostate cancer screening measure. PSA is regulated by androgens, and capsaicin limited androgen-induced increases of PSA in the cancer cell lines. Approximately 30, men die from prostate cancer in the U. Worldwide, there are , deaths — approximately 31 per cent — among men with prostate cancer.