Capsaicin induces cell cycle arrest and apoptosis in human KB cancer cells
© Lin et al.; licensee BioMed Central Ltd. 2013
Received: 25 September 2012
Accepted: 12 February 2013
Published: 25 February 2013
Capsaicin, a pungent phytochemical in a variety of red peppers of the genus Capsicum, has shown an anti-proliferative effect on various human cancer cell lines. In contrast, capsaicin has also been considered to promote the growth of cancer cells. Thus, the effects of capsaicin on various cell types need to be explored. The anti-proliferative effects of capsaicin on human KB cancer cells are still unknown. Therefore, we examined the viability, cell cycle progression, and factors associated with apoptosis in KB cells treated with capsaicin.
The cell proliferation/viability and cytotoxicity of KB cells exposed to capsaicin were determined by a sulforhodamine B colorimetric assay and trypan blue exclusion. Apoptosis was detected by Hoechst staining and confirmed by western blot analysis of poly-(ADP-ribose) polymerase cleavage. Cell cycle distribution and changes of the mitochondrial membrane potential were analyzed by flow cytometry. Furthermore, the expression of caspase 3, 8 and 9 was evaluated by immunoblotting.
We found that treatment of KB cells with capsaicin significantly reduced cell proliferation/viability and induced cell death in a dose-dependent manner compared with that in the untreated control. Cell cycle analysis indicated that exposure of KB cells to capsaicin resulted in cell cycle arrest at G2/M phase. Capsaicin-induced growth inhibition of KB cells appeared to be associated with induction of apoptosis. Moreover, capsaicin induced disruption of the mitochondrial membrane potential as well as activation of caspase 9, 3 and poly-(ADP-ribose) polymerase in KB cells.
Our data demonstrate that capsaicin modulates cell cycle progression and induces apoptosis in human KB cancer cells through mitochondrial membrane permeabilization and caspase activation. These observations suggest an anti-cancer activity of capsaicin.
KeywordsCapsaicin KB cells Cell cycle Apoptosis Mitochondria
It is well known that natural phytochemicals widely present in certain daily consumed fruits and vegetables have inhibitory effects on various types of cancers at molecular and cellular levels [1, 2]. Capsaicin, one of these naturally occurring phytochemicals, is the major pungent constituent of hot chili peppers of the genus Capsicum (family Solanaceae), which are extensively used as a food additive. It has been shown that capsaicin is involved in several physiological and pharmacological effects [3, 4]. For example, several reports show that the use of capsaicin can relieve inflammation and pain associated with some diseases and cancer [5–7]. In addition, accumulating studies have shown that capsaicin has anti-proliferative effects on various human cancer cell lines including those derived from leukemia [8–10], multiple myeloma , cutaneous cell carcinoma , glioma [13, 14], tongue cancer , nasopharyngeal carcinoma , esophageal carcinoma , gastric cancer , pancreatic cancer [19, 20], hepatocarcinoma [21, 22], colon carcinoma [23, 24], non-small cell lung cancer , breast cancer [26, 27], and prostate cancer [28, 29]. The capacity of capsaicin to suppress the growth of these cancer cells is primarily mediated through induction of apoptosis. Additionally, the activities associated with capsaicin-induced anti-cancer effects include the arrest of cell cycle progression, regulation of transcription factor expression, and suppression of growth signal transduction pathways.
The failure to control cancer cell death associated with the induction of apoptosis has been considered to be a critical cause of resistance against cancer therapy . Apoptosis, a type of programmed cell death, is a physiological homeostatic mechanism. As a result of apoptosis, unwanted cells are eliminated in a well-organized sequential process. Apoptosis is characterized by various morphological and biochemical changes such as pyknosis, plasma membrane blebbing, mitochondrial membrane permeability, and the activation of caspase cascades . It has been shown that the activation of apoptosis is mainly mediated through the extrinsic death receptor pathway and the intrinsic mitochondrial pathway, which involve a variety of caspase family members [30–32]. The extrinsic pathway is initiated by stimulation of death receptors that are members of the tumor necrosis factor receptor family. Activated death receptors induce formation of the death-inducing signaling complex (DISC) that subsequently promotes activation of caspase-8. The intrinsic pathway initiated by various intracellular signals, such as DNA damage, involves the mitochondrial response. Disruption of the mitochondrial membrane through the regulation of the Bcl-2 family members dissipates the mitochondrial transmembrane potential, resulting in the release of proapoptotic proteins, including cytochrome c and apoptosis-inducing factor, from the intermembrane space into the cytosol. Consequently, the apoptosome, a complex that stems from the interaction between cytochrome c, apoptosis protease-activating factor 1 and ATP/dATP, activates caspase-9. Both extrinsic and intrinsic pathways induce the activation of caspase 3, 6 and 7 that subsequently cleave their substrates including poly-(ADP-ribose) polymerase (PARP), ultimately leading to apoptosis.
Despite our increasing understanding of the anti-cancer effects of capsaicin on the above-mentioned cancer cell lines, capsaicin has also been found to promote the growth of cancer cells [33, 34]. The effects of capsaicin on various types of cancer need to be identified. The effect of capsaicin on human KB cancer cells remains unknown. Therefore, to gain insight into its effects, we determined whether exposure to capsaicin leads to cell cycle arrest and induction of apoptosis, and whether mitochondria and caspase members are involved in the programmed cell death. Here, we show that capsaicin induces arrest of the cell cycle at G2/M phase and causes apoptosis of KB cells. The capsaicin-induced apoptosis in KB cells is associated with mitochondrial membrane permeabilization and caspase activation. These results reveal that capsaicin may be useful for the prevention of cancer cell growth.
Cell culture and chemicals
Human KB cancer cells from the American Type Culture Collection (Manassas, VA, USA) were cultured in Dulbecco’s modified Eagle’s medium (GIBCO, Carlsbad, CA, USA) containing 10% fetal bovine serum, 100 U/ml penicillin, and 100 μg/ml streptomycin (GIBCO) at 37°C in a humidified atmosphere with 5% CO2. Capsaicin (Sigma, St. Louis, MO, USA) was dissolved in pure dimethyl sulfoxide (DMSO) (Sigma). All chemicals were of the highest grade available.
Cell viability and cytotoxicity assays
KB cells (8×103 cells/well) were seeded in 96-well plates and cultured overnight. The cells were treated with various concentrations of capsaicin (1, 50, 100, 150, 200 and 250 μM) or DMSO (control group). After 24, 48 and 72 h, cell proliferation and viability was determined by a sulforhodamine B (SRB) colorimetric assay . Briefly, the cells were fixed in 10% w/v trichloroacetic acid (Sigma) and stained with 0.4% SRB (Sigma). The cells were then washed with tap water and 1% acetic acid (Merck, Darmstadt, Germany). Protein-bound precipitates were dissolved in 10 mM Tris buffer (pH 10.5) (Merck), and the plate was read at a wavelength of 492 nm (Multiskan Spectrum Microplate Reader; Thermo Labsystems, Waltham, MA, USA) to determine the cell viability. Trypan blue exclusion was used to examine the numbers of viable and dead cells in each treatment. KB cells (1×105 cells/well) cultured in 6-well plates were treated with various concentrations of capsaicin (50, 100, 150, 200 and 250 μM) or DMSO for 24, 48 and 72 h. After harvesting, cell suspensions were thoroughly mixed with equal volumes of a 0.4% trypan blue solution (GIBCO). Viable and dead cells were counted using a hemacytometer under an inverted phase contrast microscope (Nikon Eclipse Ti-U; Nikon Instruments, Kanagawa, Japan).
Detection of apoptotic cells
Cells cultured in 24-well plates were treated with capsaicin (150 and 250 μM) or DMSO for 24 and 48 h. Following fixation in freshly prepared ice-cold 4% paraformaldehyde (Sigma) and washing with PBS, 1 μg/ml Hoechst 33342 (Cell Signaling Biotechnology Inc., Beverly, MA, USA) was used to stain the cells. Images were acquired under an inverted fluorescence microscope equipped with a digital camera (Nikon Eclipse Ti-U; Nikon Instruments). The percentage of apoptotic cells were scored by counting at least 200 cells for each treatment.
Cell cycle analysis
To detect the proportion of KB cells in different phases of the cell cycle, the DNA content in KB cells was detected by propidium iodide staining (Sigma) and flow cytometry. KB cells seeded in 6-well plates were incubated with capsaicin (150 and 250 μM) or DMSO for 24, 48 and 72 h, and then collected, washed with PBS, and fixed with 70% ethanol at −20°C overnight. After centrifugation, the cells were resuspended in PBS containing 4 μg/ml propidium iodide, 0.1 mg/ml RNase A (Amresco Inc., Solon, OH, USA) and 0.1% Triton X-100 (Sigma), and then incubated at room temperature for 1 h in the dark. Finally, the cell cycle distribution of cells from each treatment was determined by flow cytometry (Beckman FC500; Beckman Instruments, Fullerton, CA, USA) with CXP software. The percentage of cells in different phases of the cell cycle was analyzed by MultiCycle DNA Content and Cell Cycle Analysis Software.
Measurement of mitochondrial membrane potential (ΔΨm)
To elucidate the role mitochondria play in KB cell death after treatment with capsaicin, changes of the mitochondrial membrane potential were detected by flow cytometry using the fluorescent dye 3,3’-dihexyloxacarbocyanine iodide (DiOC6) (Sigma). KB cells (3×104 cells/well) were seeded in 12-well plates. After incubation with various concentrations of capsaicin (100, 200 and 250 μM) or DMSO for 24 and 48 h, the cells were washed with PBS and resuspended in 10 nM DiOC6. After incubation at 37°C for 30 min, the cells were immediately analyzed by flow cytometry.
After treatment of KB cells with capsaicin (50, 100, 150 and 250 μM) or DMSO for 24 h, the cells were collected by trypsinization, washed twice with cold PBS, and then lysed with ice-cold lysis buffer consisting of 50 mM Tris–HCl (pH 7.4), 0.1% SDS, 150 mM NaCl, 1 mM EDTA (Merck), 1% Triton X-100 and a protease inhibitor cocktail (BioVision Research Products, Mountain View, CA, USA) of 0.001% (w/v) aprotinin, 0.001% (w/v) leupeptin, 0.00035% (w/v) pepstain A, and 0.085% (w/v) PMSF. Cell lysates were kept on ice for 30 min after gentle vortexing, and then centrifuged at 11,752 g for 10 min at 4°C. The supernatants were immediately analyzed by western blotting or stored at −80°C until use. The protein concentration was measured by a Bio-Rad assay according to the manufacturer’s instructions. For western blot analysis, equal amounts of proteins (20~50 μg) from each treatment were loaded on 12% SDS-PAGE gels. SDS-PAGE and electrophoretic transfer of proteins onto PVDF membranes (Millipore, Billerica, MA, USA) were performed with Hoefer and Bio-Rad apparati, respectively. PVDF membranes were soaked for 1 h in blocking buffer consisting of 5% non-fat milk powder or 5% bovine serum albumin (Sigma) in 1× PBS containing 0.5% Tween-20. Then, PVDF membranes were incubated with antibodies against caspase 8 (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), caspase 9, caspase 3, PARP (Cell Signaling), and β-actin (Sigma) for 1 h or overnight. Membranes were then incubated with the appropriate secondary antibody conjugated to horseradish peroxidase for 1 h. After the membranes were exposed to reagents for ECL immunodetection (Millipore), the labeled proteins were detected by autoradiographic film (Eastman Kodak Co., Rochester, NY, USA).
The Student’s t-test was performed to determine the statistical significance of the difference between capsaicin- and DMSO-treated groups. Results were represented as the mean ± SD and considered significant at P < 0.05, unless stated otherwise.
Capsaicin suppresses growth and induces the death of human KB cancer cells
Capsaicin induces apoptosis in KB cells
Capsaicin induces cell cycle arrest at G2/M phase in KB cells
Capsaicin induces dissipation of the mitochondrial membrane potential (ΔΨm)
Capsaicin induces activation of caspases and PARP
Capsaicin is a naturally occurring plant phytochemical present in chili peppers. Whether it acts as a carcinogen, co-carcinogen, or anti-carcinogen is controversial [34, 35]. Nonetheless, accumulating findings indicate that capsaicin possesses anti-cancer properties in various cancer cell lines [8–29]. The goal of this study was to explore the mechanism underlying capsaicin-induced cell death in human KB cancer cells. Here, we report that treatment of KB cells with capsaicin inhibits their proliferation/viability, halts cell cycle progression, and induces apoptosis through mitochondrial membrane permeabilization and caspase activation.
In the preliminary study, we found that capsaicin treatment markedly reduced the proliferation and viability of KB cells (Figure 1), thus raising the possibility that capsaicin might be a potential chemopreventive or therapeutic agent. Several naturally occurring phytochemicals have been reported to suppress the growth of cancer cells through disruption of cell cycle progression [1, 2]. Evading cell cycle arrest is the most frequently observed phenomenon in tumor development. The cell cycle includes a number of checkpoints that act as surveillance mechanisms. Upon cellular stress or DNA damage, these mechanisms induce cells to undergo either cell cycle arrest, activation of repair systems, or apoptotic induction. Checkpoints at G1/S and G2/M transitions are essential regulatory gates during cell cycle progression [36, 37]. Numerous studies have shown a common feature in which exposure to capsaicin induces cell cycle arrest at the G1 phase in a variety of human cancer cell lines [8–12, 15–17, 22, 24, 25, 27, 28]. Interestingly, we found that G2/M phase arrest of KB cells was observed at the highest capsaicin concentration until 48 h, and no earlier cell cycle arrest was found (Figure 3). This finding suggests that the mode of capsaicin-induced cell cycle arrest depends on the cell type. Presently, the molecular mechanisms of capsaicin-induced cell cycle arrest in KB cells are unknown and require further investigation.
Apart from cell cycle arrest, induction of apoptosis is viewed as a mechanism through which a variety of naturally occurring phytochemicals inhibit tumor growth [1, 2]. Recent studies have shown that capsaicin leads to induction of apoptosis in a variety of cancer cell lines [8–29]. The data obtained in our study demonstrated dose-dependent induction of apoptosis in KB cells treated with capsaicin. We found that capsaicin triggered the activation of apoptosis prior to G2/M phase arrest in KB cells (Figures 2, 3 and 5). As mentioned above, control of cell cycle progression is a strategy to halt tumor growth [1, 2, 36, 37]. However, based on our data (Figures 1 and 3), it appears that inhibition of uncontrolled cell cycle progression plays a limited role in the inhibitory effect of capsaicin on KB cell growth. In fact, suppression of KB cell growth by capsaicin may be more correlated with induction of apoptosis.
Mitochondria-initiated responses are involved in regulation of the intrinsic apoptotic pathway [31, 32]. Furthermore, the metabolic activities of mitochondria in cancer cells are distinct from those in normal cells, and are considered to be a biologically significant source of apoptotic failure that is closely associated with chemo- and radio-resistances in cancer therapy. Therefore, induced dysfunction of mitochondria is an attractive strategy for the control of cell proliferation. The loss of mitochondrial membrane stabilization is a key event to eliminate cancer cells [38, 39]. Although exposure to capsaicin shows a slight change of mitochondrial membrane potential in MCF-7 breast cancer cells , multiple studies have revealed that capsaicin treatment leads to disruption of the mitochondrial membrane potential in various cancer cell lines [9, 10, 12, 14–17, 19, 20, 22]. These studies are consistent with our observation in which KB cells treated with capsaicin underwent loss of the mitochondrial membrane potential (Figure 4). Once the mitochondrial outer membrane is permeable, proapoptotic proteins such as cytochrome c are released into the cytosol from the intermembrane space, resulting in activation of caspase 9. Western blot analysis indicated the involvement of caspase 9 in capsaicin-induced apoptosis of KB cells (Figure 5). The other route of apoptosis, the extrinsic pathway, is initiated by the binding of ligands to death receptors. The transmembrane death signal induces formation of the DISC through adaptor proteins and subsequently leads to activation of caspase 8. Our data showed that caspase 8 did not play a role in apoptosis of KB cells treated with capsaicin (Figure 5). Both intrinsic and extrinsic pathways converge on common factors including caspase 3. Upon activation of caspases 3, substrates such as PARP are cleaved, ultimately leading to apoptotic cell death [31, 32]. Our results revealed that caspase 3 may be associated with capsaicin-induced apoptosis of KB cells (Figure 5). Collectively, mitochondria and caspase members are feasible targets of capsaicin for apoptosis of human cancer cells.
Our study indicates that exposure of human KB cancer cells to capsaicin reduces cell viability, induces cell cycle arrest at G2/M phase, and activates apoptosis that involves mitochondria and caspase members. However, capsaicin-induced cell cycle arrest may not be effective for inhibition of KB cell growth. The apoptosis of KB cells treated with capsaicin is associated with the induction of caspase 3 and 9, as well as dissipation of the mitochondrial membrane potential. In summary, these findings suggest that capsaicin possesses an anti-cancer activity and may be a potential candidate as an anti-cancer agent.
We thank Dr. Shun-Fa Yang and Dr. Shu-Fen Chiang for technical assistance. This work was financially supported by Changhua Christian Hospital.
- Chen C, Kong AN: Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects. Trends Pharmacol Sci. 2005, 26: 318-326. 10.1016/j.tips.2005.04.004.View ArticlePubMedGoogle Scholar
- Aggarwal BB, Takada Y, Oommen OV: From chemoprevention to chemotherapy: common targets and common goals. Expert Opin Investig Drugs. 2004, 13: 1327-1338. 10.1517/135437126.96.36.1997.View ArticlePubMedGoogle Scholar
- Govindarajan VS, Sathyanarayana MN: Capsicum–production, technology, chemistry, and quality. Part V. Impact on physiology, pharmacology, nutrition, and metabolism; structure, pungency, pain, and desensitization sequences. Crit Rev Food Sci Nutr. 1991, 29: 435-474. 10.1080/10408399109527536.View ArticlePubMedGoogle Scholar
- Szallasi A, Blumberg PM: Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev. 1999, 51: 159-212.PubMedGoogle Scholar
- Sancho R, Lucena C, Macho A, Calzado MA, Blanco-Molina M, Minassi A, Appendino G, Muñoz E: Immunosuppressive activity of capsaicinoids: capsiate derived from sweet peppers inhibits NF-kappaB activation and is a potent antiinflammatory compound in vivo. Eur J Immunol. 2002, 32: 1753-1763. 10.1002/1521-4141(200206)32:6<1753::AID-IMMU1753>3.0.CO;2-2.View ArticlePubMedGoogle Scholar
- Berger A, Henderson M, Nadoolman W, Duffy V, Cooper D, Saberski L, Bartoshuk L: Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy-radiation therapy. J Pain Symptom Manage. 1995, 10: 243-248. 10.1016/0885-3924(94)00130-D.View ArticlePubMedGoogle Scholar
- Hayman M, Kam PCA: Capsaicin: a review of its pharmacology and clinical applications. Curr Anest Crit Care. 2008, 19: 338-343. 10.1016/j.cacc.2008.07.003.View ArticleGoogle Scholar
- Zhang J, Nagasaki M, Tanaka Y, Morikawa S: Capsaicin inhibits growth of adult T-cell leukemia cells. Leuk Res. 2003, 27: 275-283. 10.1016/S0145-2126(02)00164-9.View ArticlePubMedGoogle Scholar
- Ito K, Nakazato T, Yamato K, Miyakawa Y, Yamada T, Hozumi N, Segawa K, Ikeda Y, Kizaki M: Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species. Cancer Res. 2004, 64: 1071-1078. 10.1158/0008-5472.CAN-03-1670.View ArticlePubMedGoogle Scholar
- Tsou MF, Lu HF, Chen SC, Wu LT, Chen YS, Kuo HM, Lin SS, Chung JG: Involvement of Bax, Bcl-2, Ca2+ and caspase-3 in capsaicin-induced apoptosis of human leukemia HL-60 cells. Anticancer Res. 2006, 26: 1965-1971.PubMedGoogle Scholar
- Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, Aggarwal BB: Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res. 2007, 13: 3024-3032. 10.1158/1078-0432.CCR-06-2575.View ArticlePubMedGoogle Scholar
- Hail N, Lotan R: Examining the role of mitochondrial respiration in vanilloid-induced apoptosis. J Natl Cancer Inst. 2002, 94: 1281-1292. 10.1093/jnci/94.17.1281.View ArticlePubMedGoogle Scholar
- Lee YS, Nam DH, Kim JA: Induction of apoptosis by capsaicin in A172 human glioblastoma cells. Cancer Lett. 2000, 161: 121-130. 10.1016/S0304-3835(00)00608-X.View ArticlePubMedGoogle Scholar
- Amantini C, Mosca M, Nabissi M, Lucciarini R, Caprodossi S, Arcella A, Giangaspero F, Santoni G: Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem. 2007, 102: 977-990. 10.1111/j.1471-4159.2007.04582.x.View ArticlePubMedGoogle Scholar
- Ip SW, Lan SH, Huang AC, Yang JS, Chen YY, Huang HY, Lin ZP, Hsu YM, Yang MD, Chiu CF, Chung JG: Capsaicin induces apoptosis in SCC-4 human tongue cancer cells through mitochondria-dependent and -independent pathways. Environ Toxicol. 2012, 27: 332-341. 10.1002/tox.20646.View ArticlePubMedGoogle Scholar
- Ip SW, Lan SH, Lu HF, Huang AC, Yang JS, Lin JP, Huang HY, Lien JC, Ho CC, Chiu CF, Wood W, Chung JG: Capsaicin mediates apoptosis in human nasopharyngeal carcinoma NPC-TW 039 cells through mitochondrial depolarization and endoplasmic reticulum stress. Hum Exp Toxicol. 2012, 31: 539-549. 10.1177/0960327111417269.View ArticlePubMedGoogle Scholar
- Wu CC, Lin JP, Yang JS, Chou ST, Chen SC, Lin YT, Lin HL, Chung JG: Capsaicin induced cell cycle arrest and apoptosis in human esophagus epidermoid carcinoma CE 81 T/VGH cells through the elevation of intracellular reactive oxygen species and Ca2+ productions and caspase-3 activation. Mutat Res. 2006, 601: 71-82. 10.1016/j.mrfmmm.2006.06.015.View ArticlePubMedGoogle Scholar
- Kim JD, Kim JM, Pyo JO, Kim SY, Kim BS, Yu R, Han IS: Capsaicin can alter the expression of tumor forming-related genes which might be followed by induction of apoptosis of a Korean stomach cancer cell line, SNU-1. Cancer Lett. 1997, 120: 235-241. 10.1016/S0304-3835(97)00321-2.View ArticlePubMedGoogle Scholar
- Zhang R, Humphreys I, Sahu RP, Shi Y, Srivastava SK: In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis. 2008, 13: 1465-1478. 10.1007/s10495-008-0278-6.View ArticlePubMedGoogle Scholar
- Pramanik KC, Boreddy SR, Srivastava SK: Role of mitochondrial electron transport chain complexes in capsaicin mediated oxidative stress leading to apoptosis in pancreatic cancer cells. PLoS One. 2011, 6: e20151-10.1371/journal.pone.0020151.View ArticlePubMedPubMed CentralGoogle Scholar
- Jung MY, Kang HJ, Moon A: Capsaicin-induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and caspase-3 activation. Cancer Lett. 2001, 165: 139-145. 10.1016/S0304-3835(01)00426-8.View ArticlePubMedGoogle Scholar
- Huang SP, Chen JC, Wu CC, Chen CT, Tang NY, Ho YT, Lo C, Lin JP, Chung JG, Lin JG: Capsaicin-induced apoptosis in human hepatoma HepG2 cells. Anticancer Res. 2009, 29: 165-174.PubMedGoogle Scholar
- Kim CS, Park WH, Park JY, Kang JH, Kim MO, Kawada T, Yoo H, Han IS, Yu R: Capsaicin, a spicy component of hot pepper, induces apoptosis by activation of the peroxisome proliferator-activated receptor gamma in HT-29 human colon cancer cells. J Med Food. 2004, 7: 267-273.View ArticlePubMedGoogle Scholar
- Lu HF, Chen YL, Yang JS, Yang YY, Liu JY, Hsu SC, Lai KC, Chung JG: Antitumor activity of capsaicin on human colon cancer cells in vitro and Colo 205 tumor xenografts in vivo. J Agric Food Chem. 2010, 58: 12999-13005. 10.1021/jf103335w.View ArticlePubMedGoogle Scholar
- Brown KC, Witte TR, Hardman WE, Luo H, Chen YC, Carpenter AB, Lau JK, Dasgupta P: Capsaicin displays anti-proliferative activity against human small cell lung cancer in cell culture and nude mice models via the E2F pathway. PLoS One. 2010, 5: e10243-10.1371/journal.pone.0010243.View ArticlePubMedPubMed CentralGoogle Scholar
- Chou CC, Wu YC, Wang YF, Chou MJ, Kuo SJ, Chen DR: Capsaicin-induced apoptosis in human breast cancer MCF-7 cells through caspase-independent pathway. Oncol Rep. 2009, 21: 665-671.PubMedGoogle Scholar
- Thoennissen NH, O'Kelly J, Lu D, Iwanski GB, La DT, Abbassi S, Leiter A, Karlan B, Mehta R, Koeffler HP: Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene. 2010, 29: 285-296. 10.1038/onc.2009.335.View ArticlePubMedGoogle Scholar
- Mori A, Lehmann S, O'Kelly J, Kumagai T, Desmond JC, Pervan M, McBride WH, Kizaki M, Koeffler HP: Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res. 2006, 66: 3222-3229. 10.1158/0008-5472.CAN-05-0087.View ArticlePubMedGoogle Scholar
- Sánchez AM, Malagarie-Cazenave S, Olea N, Vara D, Chiloeches A, Díaz-Laviada I: Apoptosis induced by capsaicin in prostate PC-3 cells involves ceramide accumulation, neutral sphingomyelinase, and JNK activation. Apoptosis. 2007, 12: 2013-2024. 10.1007/s10495-007-0119-z.View ArticlePubMedGoogle Scholar
- Fulda S, Debatin KM: Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006, 25: 4798-4811. 10.1038/sj.onc.1209608.View ArticlePubMedGoogle Scholar
- Elmore S: Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007, 35: 495-516. 10.1080/01926230701320337.View ArticlePubMedPubMed CentralGoogle Scholar
- Hengartner MO: The biochemistry of apoptosis. Nature. 2000, 407: 770-776. 10.1038/35037710.View ArticlePubMedGoogle Scholar
- Surh YJ, Lee SS: Capsaicin in hot chili pepper: carcinogen, co-carcinogen or anticarcinogen?. Food Chem Toxicol. 1996, 34: 313-316. 10.1016/0278-6915(95)00108-5.View ArticlePubMedGoogle Scholar
- Bode AM, Dong Z: The two faces of capsaicin. Cancer Res. 2011, 71: 2809-2814. 10.1158/0008-5472.CAN-10-3756.View ArticlePubMedGoogle Scholar
- Vichai V, Kirtikara K: Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006, 1: 1112-1116. 10.1038/nprot.2006.179.View ArticlePubMedGoogle Scholar
- Hartwell LH, Kastan MB: Cell cycle control and cancer. Science. 1994, 266: 1821-1828. 10.1126/science.7997877.View ArticlePubMedGoogle Scholar
- Kastan MB, Bartek J: Cell-cycle checkpoints and cancer. Nature. 2004, 432: 316-323. 10.1038/nature03097.View ArticlePubMedGoogle Scholar
- Gogvadze V, Orrenius S, Zhivotovsky B: Mitochondria in cancer cells: what is so special about them?. Trends Cell Biol. 2008, 18: 165-173. 10.1016/j.tcb.2008.01.006.View ArticlePubMedGoogle Scholar
- Costantini P, Jacotot E, Decaudin D, Kroemer G: Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst. 2000, 92: 1042-1053. 10.1093/jnci/92.13.1042.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6882/13/46/prepub
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