curcumin and Kidney-Neoplasms

Dimethylcurcumin (ASC-J9) is a curcumin analogue capable of inhibiting prostate cancer cell proliferation. The mechanism is associated with the unique role of ASC-J9 in enhancing androgen receptor (AR) degradation. So far, ASC-J9 has been investigated in typical AR-associated diseases such as prostate cancer, benign prostatic hypertrophy, bladder cancer, renal diseases, liver diseases, cardiovascular diseases, cutaneous wound, spinal and bulbar muscular atrophy, ovarian cancer and melanoma, exhibiting great potentials in disease control. In this review, the effects and molecular mechanisms of ASC-J9 on various AR-associated diseases are summarized. Importantly, the effects of ASC-J9 and AR antagonists enzalutamide/bicalutamide on prostate cancer are compared in detail and crucial differences are highlighted. At last, the pharmacological effects of ASC-J9 are summarized and the future applications of ASC-J9 in AR-associated disease control are discussed.

Topics: Androgen Receptor Antagonists; Curcumin; Humans; Kidney Neoplasms; Male; Prostatic Neoplasms; Radiation Tolerance; Receptors, Androgen; Signal Transduction; Urinary Bladder Neoplasms

To explore the effect of curcumin on the proliferation of renal cell carcinoma and analyze its regulation mechanism.. In RCC cell lines of A498 and 786-O, the effects of curcumin (2.5, 5, 10 µ mo/L) on the proliferation were analyzed by Annexin V+PI staining. Besides, A498 was inoculated into nude mice to establish tumorigenic models, and the model mice were treated with different concentrations of curcumin (100, 200, and 400 mg/kg), once daily for 30 days. Then the tumor diameter was measured, the tumor cells were observed by hematoxylin-eosin staining, and the protein expressions of miR-148 and ADAMTS18 were detected by immunohistochemistry. In vitro, after transfection of miR-148 mimics, miR-148 inhibitor or si-ADAMTS18 in cell lines, the expression of ADAMTS18 was examined by Western blotting and the cell survival rate was analyzed using MTT. Subsequently, Western blot analysis was again used to examine the autophagy phenomenon by measuring the relative expression level of LC3-II/LC3-I; autophagy-associated genes, including those of Beclin-1 and ATG5, were also examined when miR-148 was silenced in both cell lines with curcumin treatment.. Curcumin could inhibit the proliferation of RCC in cell lines and nude mice. The expression of miR-148 and ADAMTS18 was upregulated after curcumin treatment both in vitro and in vivo (P<0.05). The cell survival rate was dramatically declined upon miR-148 or ADAMTS18 upregulated. However, si-ADAMTS18 treatment or miR-148 inhibitor reversed these results, that is, both of them promoted the cell survival rate.. Curcumin can inhibit the proliferation of renal cell carcinoma by regulating the miR-148/ ADAMTS18 axis through the suppression of autophagy in vitro and in vivo. There may exist a positive feedback loop between miR-148 and ADAMTS18 gene in RCC.

Topics: ADAMTS Proteins; Animals; Autophagy; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Kidney Neoplasms; Mice; Mice, Nude; MicroRNAs

The mechanism of curcumin inhibiting renal cancer 786-O cells proliferation through MTOR signaling pathway was investigated.. Human renal cancer 786-O cells were cultured with curcumin for 48 h. The OD values were measured by the MTT method, and the growth inhibition rate of 786-O cells was calculated. The cell cycle distribution and apoptosis rate were detected by flow cytometry (FCM). Transwell chamber was introduced to detect cell invasion ability. Cell migration ability was detected by the cell scratch test. The protein expression was assessed by Western blot.. With curcumin concentration increasing, the expressions of MMP2, MMP9, MTOR, and p-MTOR proteins and the number of cells in the S phase decreased gradually, while number of cells in G1 and G2/M phases and cells apoptosis rate increased continuously. With the increasing of concentration and time, growth of 786-O cells in each treatment group was inhibited to varying degrees. The higher the inhibition rate was, the cells migration and transmembrane cells proportion decreased significantly.. Curcumin inhibits the proliferation, migration, and invasion and induces apoptosis of renal cancer 786-O cells by blocking the MTOR signaling pathway. It may be related to the downregulation of MMP2 and MMP9 proteins.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Kidney Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Signal Transduction; TOR Serine-Threonine Kinases

To investigate the effect of curcumin on viability of clear cell renal cell carcinoma (ccRCC) and analyze its possible mechanism.. In cell lines of A498 and 786-O, the effects of curcumin (1.25, 2.5, 5 and 10 μ mol/L) on the viability of ccRCC were analyzed at 24, 48 and 72 h by MTT assay. The protein expression levels of ADAMTS18 gene, p65, phosphorylation p65 (pp65), AKT, phosphorylation AKT (pAKT) and matrix metallopeptidase 2 (MMP-2) before and after curcumin (10 μ mol/L) treatment were examined by Western blotting. Real-time PCR and methylation specific PCR (MSP) were applied to analyze the expression and methylation level of ADAMTS18 gene before and after curcumin treatment (10 μ mol/L).. Curcumin significantly inhibited the viability of A498 and 786-O cell lines in a dose- and time-dependent manner (P<0.01). Up-regulation of ADAMTS18 gene expression with down-regulation of ADAMTS18 gene methylation was reflected after curcumin treatment, accompanied by down-regulation of nuclear factor κ B (NF-κ kB) related protein (p65 and pp65), AKT related protein (AKT and pAKT), and NF-κ B/AKT common related protein MMP-2. With ADAMTS18 gene overexpressed, the expression levels of p65, AKT and MMP2 were downregulated, of which were conversely up-regulated in silenced ADAMTS18 (sh-ADAMTS18). The expression of pp65, pAKT and MMP2 in sh-ADAMTS18 was down-regulated after being treated with PDTC (NF-κ B inhibitor) and LY294002 (AKT inhibitor).. Curcumin could inhibit the viability of ccRCC by down-regulating ADAMTS18 gene methylation though NF-κ B and AKT signaling pathway.

Topics: ADAMTS Proteins; Carcinoma, Renal Cell; Cell Line, Tumor; Curcumin; DNA Methylation; Female; Humans; Kidney Neoplasms; Male; Matrix Metalloproteinase 2; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction

Epidemic modeling has been a key tool for understanding the impact of global viral outbreaks for over two decades. Recent developments of the COVID-19 pandemic have accelerated research using compartmental models, like SI, SIR, SEIR, with their appropriate modifications. However, there is a large body of recent research consolidated on homogeneous population mixing models, which are known to offer reduced tractability, and render conclusions hard to quantify. As such, based on our recent work, introducing the heterogeneous geo-spatial mobility population model (GPM), we adapt a modified SIR-V (susceptible-infected-recovered-vaccinated) epidemic model which embodies the idea of patient relapse from R back to S, vaccination of R and S patients (reducing their infectiousness), thus altering the infectiousness of V patients (from

Topics: Acute Lung Injury; Adherens Junctions; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antigens, CD; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; beta Catenin; Brain Ischemia; Cadherins; Carcinogenesis; Catalysis; Cell Line; Cells, Cultured; Curcuma; Curcumin; Dioxoles; Disease Models, Animal; Endothelial Cells; Epithelial Cells; Heme Oxygenase (Decyclizing); Humans; Inflammasomes; Intestinal Diseases; Intestinal Mucosa; Ischemic Stroke; Kidney Neoplasms; Lignans; Lung; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; NAD(P)H Dehydrogenase (Quinone); Nanostructures; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phytotherapy; Plant Extracts; Pneumonia; PPAR gamma; Proto-Oncogene Proteins c-akt; Pyroptosis; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reperfusion Injury; Respiratory Distress Syndrome; Sepsis; Sesamum; Signal Transduction; Silybin; Silybum marianum; Silymarin; Sirtuin 3; Titanium; Transfection; Treatment Outcome; White Matter

Curcumin (Cur), is a pigment with antiproliferative activity but has some pharmacokinetic limitations, which led researchers to look for more effective structure analogs. This work investigated the effects of Cur and compared them with the two analogs, demethoxycurcumin (DeMC) and dimethoxycurcumin (DiMC), to elucidate their mechanisms of action. The cytotoxic, antiproliferative, and genotoxic effects these compounds were correlated based on gene expression analysis in the human renal adenocarcinoma cells (786-O). Cur decreased CYP2D6 expression and exhibited cytotoxic effects, such as inducing monopolar spindle formation and mitotic arrest mediated by the increase in CDKN1A (p21) mRNA. This dysregulation induced cell death through a caspase-independent pathway but was mediated by decrease in MTOR and BCL2 mRNA expression, suggesting that apoptosis occurred by autophagy. DeMC and DiMC had similar effects in that they induced monopolar spindle and mitotic arrest, were genotoxic, and activated GADD45A, an important molecule in repair mechanisms, and CDKN1A. However, the induction of apoptosis by DeMC was delayed and regulated by the decrease of antiapoptotic mRNA BCL.XL and subsequent activation of caspase 9 and caspase 3/7. DiMC treatment increased the expression of CYP1A2, CYP2C19, and CYP3A4 and exhibited higher cytotoxicity compared with other compounds. It induced apoptosis by increasing mRNA expression of BBC3, MYC, and CASP7 and activation of caspase 9 and caspase 3/7. These data revealed that different gene regulation processes are involved in cell death induced by Cur, DeMC, and DiMC. All three can be considered as promising chemotherapy candidates, with DiMC showing the greatest potency.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Comet Assay; Curcumin; Diarylheptanoids; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Spindle Apparatus

This study was designed to reveal the protective effects of dietary supplementation of curcumin against renal cell tumours and oxidative stress induced by renal carcinogen iron nitrilotriacetate (Fe-NTA) in ddY male mice. The results showed that mice treated with a renal carcinogen, Fe-NTA, a 35% renal cell tumour incidence was noticed, whereas renal cell tumour occurrence was elevated to 80% in Fe-NTA promoted and N-diethylnitrosamine (DEN)-initiated mice as compared with saline- treated mice. No incidence of tumours has been observed in DEN-initiated non-promoted mice. Diet complemented with 0.5% and 1.0% curcumin fed prior to, during and after treatment with Fe-NTA in DEN-initiated animals, tumour incidence was reduced dose-dependently to about 45% and 30% respectively. Immunohistochemical studies also revealed the increased formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in kidney tissue of mice treated with an intraperitoneal injection of Fe-NTA (6.0 mg Fe/kg body weight.). Furthermore, Fe-NTA treatment of mice also resulted in significant elevation of malondialdehyde (MDA), serum urea, and creatinine and decreases renal glutathione. However, the changes in most of these parameters were attenuated dose-dependently by prophylactic treatment of animals with 0.5% and 1% curcumin diet, this may be due to its antioxidative impact of curcumin. These results suggest that intake of curcumin is beneficial for the prevention of renal cell tumours and oxidative stress damage mediated by renal carcinogen, Fe-NTA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Blood Urea Nitrogen; Carcinogens; Carcinoma, Renal Cell; Creatinine; Curcumin; Diet; Diethylnitrosamine; Dose-Response Relationship, Drug; Ferric Compounds; Kidney Neoplasms; Male; Mice; Nitrilotriacetic Acid; Oxidative Stress

Curcumin has a vital role in the development of renal carcinoma. Nevertheless, the mechanism of curcumin in renal carcinoma tumorigenesis remains largely unknown. Thirty renal carcinoma patients were recruited. Renal carcinoma cell lines CAKI-1 and ACHN were exposed to curcumin. The levels of circular RNA fibronectin type III domain-containing protein 3B (circ-FNDC3B), microRNA (miR)-138-5p and insulin-like growth factor 2 (IGF2) were detected via quantitative reverse transcription PCR or western blot. Cell proliferation and apoptosis were investigated via 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide, colony formation analysis, flow cytometry and western blot. Target association between miR-138-5p and circ-FNDC3B or IGF2 was analyzed via dual-luciferase reporter analysis. The function of curcumin in vivo was assessed via a xenograft model. circ-FNDC3B level was enhanced and miR-138-5p abundance was declined in renal carcinoma tissues and cells. Curcumin restrained renal carcinoma cell proliferation and promoted apoptosis. circ-FNDC3B overexpression or miR-138-5p knockdown weakened the influence of curcumin. circ-FNDC3B knockdown hindered cell proliferation and promoted apoptosis by increasing miR-138-5p. IGF2 was targeted via miR-138-5p and positively regulated via circ-FNDC3B. Curcumin decreased xenograft tumor growth via reducing circ-FNDC3B in vivo. Curcumin suppressed renal carcinoma tumorigenesis in vitro and in vivo via regulating circ-FNDC3B/miR-138-5p/IGF2 axis, proposing new insight into renal carcinoma tumorigenesis.

Topics: Animals; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Fibronectins; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor II; Kidney Neoplasms; Mice; Mice, Inbred BALB C; MicroRNAs; Signal Transduction; Xenograft Model Antitumor Assays

Renal cell carcinoma (RCC) is a highly aggressive cancer leading to high economic and social burden, and has increasing annual cases. Curcumin is a traditional Chinese medicine widely used as anti-inflammatory, anti-viral and anti-cancer agent, thus can be applicable in RCC therapy. The work assessed the effects of RCC treatment with Curcumin, Curcumin+3-MA, Curcumin+ CQ or curcumin+ Z-VAD in vitro and in vivo, and the mechanisms involved in inhibition of tumor cells proliferation. The study used ACHN tumor cells and C57BL/6 nude mice for results validation. Cell proliferation was determined through MTT assays while apoptosis was investigated using Annexin V-FITC/PI kit and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to detect IL-6, IL-8, and TNF-α cytokines expressions. AKT/mTOR and autophagy proteins expressions were investigated through western blot and immunofluorescence. The results indicated significantly inhibited cell viability following ACHN tumor cells treatments with curcumin alone, or with the various combinations, as compared to the control. Apoptosis was significantly increased following curcumin treatment, but was significantly reversed after treatment with curcumin+ 3-MA. Likewise, AKT/mTOR proteins expression were significantly reduced while the autophagy-related proteins were significantly elevated following curcumin treatment. The tumor size, weight and volumes were also significantly suppressed following treatment with curcumin. In conclusion, the investigation demonstrated that curcumin suppressed ACHN cell viability, induced apoptosis and autophagy, through the suppression of AKT/mTOR pathway. Use of curcumin to target AKT/mTOR pathway could be an effective treatment alternative for renal cell carcinoma.

Topics: Animals; Apoptosis; Autophagy; Cell Line, Tumor; Curcumin; Cytokines; Humans; Kidney Neoplasms; Mice; Mice, Nude; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Long non-coding RNAs (lncRNAs) have been demonstrated to exert important roles in cancer development and progression. The biological function of lncRNA X-inactive specific transcript (XIST) in the development of renal cell carcinoma (RCC) and the underlying mechanisms are still largely unknown. In this study, we found that XIST was down-regulated in RCC tissues and cells. Overexpression of XIST significantly suppressed cell proliferation and induced cell G0/G1 arrest in vitro and inhibited tumor growth in vivo. We further found that XIST could directly interact with miR-106b-5p and increase the expression of P21. Thus, XIST positively regulated the expression of P21 through sponging miR-106b-5p, and played a tumor suppressor role in RCC. Moreover, we found that curcumin could regulate XIST/miR-106b-5p/P21 axis in RCC cells. Our study exhibits the role of XIST as a miRNA sponge in RCC and supports the potential application of XIST in RCC therapy.

Topics: Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Disease Progression; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Mice, Inbred BALB C; MicroRNAs; Resting Phase, Cell Cycle; RNA, Long Noncoding

Wilms' tumor (WT) is the most common kidney tumor of children. The transformation suppressor gene RECK, which codes membrane-anchored glycoprotein, frequently downregulates multiple matrix metalloproteinases in tumors. And curcumin, which is a polyphenlic compound separated from turmeric, has antitumor effects on various cancers. However, the correlation of WT, RECK and curcumin is still unrevealed. In this study, we evaluated that the methylation degree of RECK was much higher in WT than in adjacent non-tumor tissues. And RECK methylation was closely associated with tumor metastasis in WT patients. After curcumin treatment, the level of RECK methylation was decreased significantly. And the expression of MMP2 and MMP9 was reduced consequently. Moreover, the proliferation, invasion and migration ability of WT cells were suppressed after curcumin treatment. Meanwhile, the apoptosis rate of WT cells was increased simultaneously. In nude mice model, curcumin restrained ability of tumorigenicity and promoted apoptosis of WT cells. Together, our results suggest that the RECK methylation can serve as a prognostic biomarker of WT. Moreover, curcumin could inhibit RECK methylation, thereby abates the expression of MMPs, and suppresses the tumor progression and metastasis of WT.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Carcinogenesis; Cell Movement; Cell Proliferation; Child, Preschool; Curcumin; DNA Methylation; Down-Regulation; Female; GPI-Linked Proteins; Humans; Kidney Neoplasms; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Metastasis; Wilms Tumor

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Nucleus; Curcuma; Gene Expression Regulation, Neoplastic; Gold; Humans; Kidney Neoplasms; Metal Nanoparticles; Mitochondria; Plant Extracts; Reactive Oxygen Species; Spectroscopy, Fourier Transform Infrared

The aim of this study was to explore the effects of curcumin on renal cell carcinoma（RCC） through regulating autophagy. Cell viabilities were determined by MTT assay in RCC cells after treatment with curcumin at different concentrations for various durations. ATG7 silencing RCC cells were established to test the role of autophagy. The levels of key proteins on autophagy pathway were analyzed by Western blot. We found out that following 24 h curcumin treatment, the viability of RCC cells had an increase at 5 μM and no significant change at 20 μM but a decrease at 80 μM. These effects were affected by the inhibition of autophagy. When pre-incubated with inhibitors of the AMPK and ER stress pathways, the LC3II levels of RCC cells at 5 μM and 20 μM of curcumin were significantly decreased; however, when treated with the inhibitor of the oxidative stress pathway, the LC3II levels of RCC cells at 80 μM were significantly decreased. In conclusion, the present study indicated Curcumin protected cells from death at low concentration but promotes cell death at high concentration. Autophagy played a dual role in curcumin's effects on RCC. The AMPK and ER stress pathways might be involved at low concentrations of curcumin to protect cells, while the oxidative stress pathway might take part in toxicity at high curcumin concentration.

Topics: Acetylcysteine; AMP-Activated Protein Kinases; Antineoplastic Agents; Autophagy; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Curcumin; Endoplasmic Reticulum Stress; Humans; Kidney Neoplasms; Oxidative Stress; Phenylbutyrates; Pyrazoles; Pyrimidines; Signal Transduction

Curcumin possesses anti-cancer effects. In the current study, we tested the effect of curcumin on cell proliferation, viability, apoptosis, cell cycle phases, and activation of the PI3K/Akt pathway in the renal cell carcinoma (RCC) cell line RCC-949. We observed that cell proliferation and viability were markedly inhibited by curcumin, while cell apoptosis was promoted. The latter effect was associated with increased expression of Bcl-2 and diminished expression of Bax (both: mRNA and protein). The cells treated with curcumin increasingly went into cell cycle arrest, which was likely mediated by diminished expression of cyclin B1, as seen in curcumin-treated cells. In addition, curcumin decreased activation of the PI3K/AKT signaling pathway. In conclusion, our results demonstrate that curcumin exerts anti-cancer effects by negative modulation of the PI3K/AKT signaling pathway and may represent a promising new drug to treat RCC.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Renal Cell; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Kidney Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Males have a higher incidence of renal cell carcinoma (RCC) than females, but the reason for this gender difference is unknown. Addressing this question, we report the discovery of an androgen receptor (AR)-induced HIF2α/VEGF signal that drives RCC progression. AR attenuation or augmentation in RCC cells altered their proliferation, migration, and invasion in multiple models in vitro and in vivo. Mechanistic investigations revealed that AR targeting inhibited RCC cell migration and invasion by modulating HIF2α/VEGF signals at the level of mRNA and protein expression. Interrupting HIF2α/VEGF signals with inhibitors of either HIF2α or VEGF was sufficient to suppress RCC progression. Similarly, the specific AR degradation enhancer ASC-J9 was sufficient to suppress AR-induced HIF2α/VEGF signaling and RCC progression in multiple models in vitro and in vivo. Taken together, our results revealed a novel role for AR in RCC initiation and progression with implications for novel therapeutic strategies.

Topics: Animals; Carcinoma, Renal Cell; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Curcumin; Disease Progression; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Male; Mice; Mice, Nude; Signal Transduction; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

This study investigated the influence of curcumin on HOX transcript antisense RNA (HOTAIR)- mediated migration of cultured renal cell carcinoma (RCC) cells.. Five RCC cell lines (769-P, 769-P-vector, 769-P-HOTAIR, 786-0, and Kert-3 ) were maintained in vitro. The expression of HOTAIR mRNA was determined by quantitative real-time PCR and cell migration was measured by transwell migration assay. The effects of different concentrations of curcumin (0 to 80 μmol/L) on cell proliferation was determined by the CCK-8 assay and influence of non-toxic levels (0 to 10 μM) on the migration of RCC cells was also determined.. Comparison of the 5 cell lines indicated a correlation between HOTAIR mRNA expression and cell migration. In particular, the migration of 769-P-HOTAIR cells was significantly higher than that of 769-P-vector cells. Curcumin at 2.5-10 μM had no evident toxicity against RCC cells, but inhibited cell migration in a concentration-dependent manner.. HOTAIR expression is correlated with the migration of RCC cells, and HOTAIR may be involved in the curcumin-induced inhibition of RCC metastasis.

Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; RNA, Long Noncoding

Topics: Animals; Carcinoma, Renal Cell; Curcumin; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Male; Vascular Endothelial Growth Factor A

Curcumin, a natural, biologically active compound extracted from rhizomes of Curcuma species, has been shown to possess potent anti-inflammatory, anti-tumor and anti-oxidative properties. The mechanism by which curcumin initiates apoptosis remains poorly understood. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human renal Caki cells. Treatment of Caki cells with 50 microM curcumin resulted in the activation of caspase 3, cleavage of phospholipase C-gamma1 and DNA fragmentation. Curcumin-induced apoptosis is mediated through the activation of caspase, which is specifically inhibited by the caspase inhibitor, benzyloxycarbony-Val-Ala-Asp-fluoromethyl ketone. Curcumin causes dose-dependent apoptosis and DNA fragmentation of Caki cells, which is preceded by the sequential dephosphorylation of Akt, down-regulation of the anti-apoptotic Bcl-2, Bcl-XL and IAP proteins, release of cytochrome c and activation of caspase 3. Cyclosporin A, as well as caspase inhibitor, specifically inhibit curcumin-induced apoptosis in Caki cells. Pre-treatment with N-acetyl-cysteine, markedly prevented dephosphorylation of Akt, and cytochrome c release, and cell death, suggesting a role for reactive oxygen species in this process. The data indicate that curcumin can cause cell damage by inactivating the Akt-related cell survival pathway and release of cytochrome c, providing a new mechanism for curcumin-induced cytotoxicity.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Blotting, Western; Carcinoma, Renal Cell; Caspases; Curcumin; Cytochrome c Group; Down-Regulation; Enzyme Activation; Enzyme Inhibitors; Free Radical Scavengers; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Kidney Neoplasms; Mitochondria; Poly(ADP-ribose) Polymerases; Protein Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Curcumin, which is a widely used dietary pigment and spice, has been demonstrated to be an effective inhibitor of tumor promotion in mouse skin carcinogenesis. We report that curcumin induces cell shrinkage, chromatin condensation, and DNA fragmentation, characteristics of apoptosis, in immortalized mouse embryo fibroblast NIH 3T3 erb B2 oncogene-transformed NIH 3T3, mouse sarcoma S180, human colon cancer cell HT-29, human kidney cancer cell 293, and human hepatocellular carcinoma Hep G2 cells, but not in primary culture of mouse embryonic fibroblast C3H 10T1/2, rat embryonic fibroblast, and human foreskin fibroblast cells in a concentration- and time-dependent manner. Many cellular and biochemical effects of curcumin in mouse fibroblast cells have been reported, such as inhibition of protein kinase C (PKC) activity induced by phorbol 12-myristate 13-acetate treatment, inhibition of tyrosine protein kinase activity, and inhibition of arachidonic acid (AA) metabolism. Treatment of NIH 3T3 cells with the PKC inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin A, and the AA metabolism inhibitor quinacrine induces apoptotic cell death. These results suggest that, in some immortalized and transformed cells, blocking the cellular signal transduction might trigger the induction of apoptosis.

Topics: 3T3 Cells; Animals; Apoptosis; Carcinoma, Hepatocellular; Chromatin; Colonic Neoplasms; Curcumin; DNA Fragmentation; Humans; Kidney Neoplasms; Liver Neoplasms; Mice; Rats; Sarcoma, Experimental; Signal Transduction; Tumor Cells, Cultured