Yes! and Yes! Here is what I have on curcumin, includes dose.
Curcumin contains several polyphenols, including chlorogenic, caffeic and ferulic acids, but its benefits go way beyond its polyphenols. It has generated significant interest iin cancer researchers around the world, exhibiting a variety of cancer-inhibiting properties, including anti-estrogenic activity 1. Curcumin inhibits cancer through multiple mechanisms, including antioxidant activity at low doses and pro-oxidant actions at high doses. It induces glutathione S-transferase enzymes and acts as an anti-inflammatory. Curcumin inhibits binding of oncogens like cytochrome P450 enymes to DNA and suppresses angiogensis by inhibiting kinases, interleukin-1 (IL-1)-alpha as well as tumor necrosis factor-(TNF)-activated NF-kappaB. It also exhibits an inhibitory effect on prostaglandin E(2).
Curcumin has been found effective against a number of cancer cell lines and has shown a remarkable ability to sensitize cancer cells to several chemotherapy drugs, including Taxol, platinum drugs and radiation treatment. Researchers believe the enhanced effect on chemotherapy drugs is due to curcumin’s downregulation of pro-survival communication pathways, including Akt and nuclear factor kB 2.
Taxol, like many chemotherapeutic agents, provokes anti-apoptotic proteins like nuclear factor-kappa B (NF-kB) 3, which lead to drug resistance. Numerous studies confirm curcumin’s ability to suppress these proteins.
A study lead by Bharat B. Aggarwal, Ph.D from M.D. Anderson Cancer Center in Houston, Texas found curcumin’s suppression of Taxol-induced NF-kB inhibited metastasis of breast cancer in mice.
Our study indicates that paclitaxel activates NF-nB in human breast cancer cells through a classic NF-nB activation pathway consisting of IKK activation, InBa phosphorylation and degradation, and NF-nB–regulated gene expression, including cyclin D1, MMP-9, and COX-2. Treatment of breast cancer cells with curcumin completely suppressed the paclitaxelinduced IKK activation, leading to suppression of NF-nB activation. Curcumin also suppressed paclitaxel-induced cyclin D1, MMP-9, and COX-2 in breast cancer cells. Paclitaxel also induced various antiapoptotic gene products in these cells and again their expression was down-regulated by curcumin. Our results are in agreement with previous reports that showed that curcumin inhibits COX-2 (8, 18), cyclin D1 (19), and MMP-9 (20) expression, all of which are regulated by NF-nB. …Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-nB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-nB and NF-nB ^ regulated gene products.
Curcumin Suppresses the Paclitaxel-Induced Nuclear Factor-KB Pathway in Breast Cancer Cells and Inhibits Lung Metastasis Of Human Breast Cancer inNudeMice, Oct 15;11 (20): Clin Cancer Res. 2005 749008
A study bt the Division of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India found that treating cervical and kidney cancer cells with curcumin caused enhancd Taxol-mediated growth arrest. Again, curcumin’s suppression of Taxol-activated NF-kB is thought greatly responsible for inhibition of pro-survival oncogenes.
The primary mechanism of the action of Taxol is attributed to its ability to bind to microtubules and prevent their assembly, causing cells to arrest in the G2/M phase and thereby blocking cell cycle progression (6). Although this explains the underlying mechanism of Taxol-mediated growth arrest, its efficacy exceeds that of conventional microtubule-disrupting agents, suggesting that additional cellular effects may be operating via pathways independent of mitotic arrest (33, 34). Our results also support this notion. We observed a dose-dependent cytotoxic effect by Taxol in HeLa cells, which was potentiated by pre-treatment with 5 µM curcumin. We provide herein proof of the principle of curcumin pre-treatment augmenting membrane flip-flop, caspase activation, PARP cleavage, and cytochrome c release by Taxol. Throughout the present study we did not see a noticeable apoptosis induction by curcumin alone (5 µM), even though we noticed induction of all of the above-mentioned apoptotic parameters by curcumin at a higher concentration of 25 µM (21).
Tumor cells often evade apoptosis by overexpressing antiapoptotic proteins such as Bcl-2, NF- B, Akt, etc., which give them a survival advantage (35–37). Some conventional chemotherapeutic drugs in low concentrations cause up-regulation of survival signals, thereby necessitating increment of the effective dose of treatment. We have previously reported the protective effect of NF- B against apoptosis (18). Taxol activates NF- B in several cell systems, probably through the principal kinase IKK- (26). On the contrary, curcumin promotes apoptosis reportedly by interfering in cell survival signaling pathways (17, 21, 38, 39). It inhibits the NF- B pathway at a step before I B phosphorylation (17) by inhibiting IKK activity, probably via a NIK-IKK signaling complex (40). Several research groups, including ours, have reported that curcumin inhibits NF- B activation induced by various agents (17, 18, 41). In the present study we observed that Taxol-induced NF- B activation in HeLa cells is down-regulated by curcumin, which mechanistically may be contributing to the sensitization of HeLa cells to Taxol-induced apoptosis. Interestingly, Taxol per se could not activate NF- B in normal cervical cells or in human 293 cells in which Taxol down-regulates NF- B. This highlights the possible reason for the absence of a synergistic effect in these cells. The involvement of this mechanism was further confirmed when we could not find any synergistic effect in HeLa-I B cells even though they became sensitive to lower concentrations of Taxol, supporting our earlier studies (23). As we have used a non-toxic concentration of curcumin in this study, an additive effect in terms of cytotoxicity of both the compounds cannot be expected.
Studies published previously describe Taxol as an activator of Akt, a serine/threonine protein kinase and a downstream target of phosphoinositide 3-kinase (42, 43). We observed down-regulation of Taxol-induced Akt activation by curcumin in HeLa cells. Many workers have shown that Akt suppresses apoptosis by activating NF- B (30, 31). According to a recent report, treatment with LY294002, a specific inhibitor of phosphoinositide 3-kinase, resulted in enhancement of Taxol-induced cytotoxicity followed by suppression of NF- B transcriptional activity, indicating that NF- B may be the crucial intermediary step connecting Akt to the intrinsic susceptibility of cancer cells to chemotherapeutic agents (44). Inhibition of Akt by curcumin and its derivatives is also known (38, 45, 46). But whether Taxol-induced up-regulation and curcumin-induced down-regulation of Akt is regulated only through NF- B is neither clear from these studies nor from ours. However, several studies have shown that Taxol directly activates the survival pathways such as Bcl-2, Akt, Cox-2, mitogen-activated protein kinase, etc. (42, 47, 48) independently of NF- B. Moreover, Taxol did not induce Akt activation in normal cells, which also may be a contributing factor for the absence of synergistic effect of Taxol and curcumin in these cells. Furthermore, control experiments indicate that curcumin alone did not lead to apoptosis but that it is the pretreatment that caused sensitization, leading to down-regulation of NF- B and Akt, augmenting apoptosis.
Some retinoids have been reported to have synergistic cytotoxic effects with Taxol independent of tubulin polymerization (49). To see whether curcumin is inducing any cell cycle-specific effects and influencing the tubulin polymerization induced by Taxol in HeLa cells, we examined the level of polymerized and non-polymerized tubulin in cells exposed to curcumin and/or Taxol.
Our results indicate that curcumin does not interfere with the tubulin-polymerizing action of Taxol at the investigated concentration (5 µM), although Holy (50) observed disruption of mitotic spindle structure and induction of micronucleation by curcumin at a higher concentration (25 µM). Up-regulation of the cell cycle protein Cdc2 by Taxol plays a critical role in Taxol-induced mitotic arrest (51). We did not observe any noticeable effect of curcumin on Taxol-induced Cdc2 synthesis, even though Jaiswal et al. (52) have reported a slight down-regulation of Cdc2 by curcumin at a higher concentration (20 µM). These results lead to the conclusion that the synergistic effect of Taxol and curcumin in inducing apoptosis in cervical cancer cells follows a pathway that is independent of tubulin polymerization and cell cycle arrest, at least at lower concentrations of curcumin.
Sensitization of Taxol-induced Apoptosis by Curcumin Involves Down-regulation of Nuclear Factor- B and the Serine/Threonine Kinase Akt and Is Independent of Tubulin Polymerization, J. Biol. Chem., Vol. 280, Issue 8, 6301-6308, February 25, 2005
Results of a study using curcumin on colorectal cancer cells “suggest that curcumin potentiates the antitumor effects of radiation therapy in colorectal cancer by suppressintg NF-kB and NF-kB-regulated gene products, leading to inhibition of proliferation and angiogenisis 4”
A study on liver cancer cells found curcumin induced apoptosis independently, but when it was combined with Cisplatin curcumin “showed a synergistic antitumor activity 5.”
A study of curcumin’s effects on ovarian cancer determined “that 500 mg/dg orally was the optimal dose needed to suppress NF-kB and signal transducers and activators of transcription 3 activation and decrease angiogenic cytokine expression… Curcumin alone resulted in 49% (P=0.08) and 55% (p=0.01) reductions in mean tumor growth compared with controls, wheras when combined with cocetaxel elicited 96% (,0.001) and 77% reductions in mean tumor growth compared with controls 7.”
Contrary to previous research, a study on breast cancer cells found that curcumin inhibits chemotherapy-induced apoptosis. The study concluded that curcumin caused an inhibition of “the generation of reactive oxygen species (ROS) and the JNK pathway; and because many chemotherapeutic drugs generate ROS and activate JNK in the course of inducing apoptosis, we considered the possibility that curcumin might antagonize their antitumor effacy 8.”
An objection to that study presented as a letter to the editor points to several mistaken assumptions of the study. One very helpful criticism for those seeking to benefit from the use of curcumin is the commentary on dosage. The letter noted that the study failed to realize that curcumin works as an antioxidant at low doses and as a pro-oxidant at high doses and that an inappropriate dose would produce an undesired result.
Contrary to the findings of the present study, curcumin has been shown to augment the cytotoxic effects of chemotherapeutic drugs, including doxorubicin 1 , tamoxifen 2 , cisplatin and camptothecin 3 , daunorubicin, vincristine, and melphalan 4 . Navis et al. 5 reports that curcumin normalizes elevations in tumor-related enzymes when combined with cisplatin, leading to the inference that it will be a good adjuvant for this drug as well. There appear to be methodological problems with the present study that cause results that conflict with these and other published studies.
The dose of curcumin used in the study may be insufficient for the purpose it’s intended. It is well established that curcumin has distinct dose-related behavior. For example, treatment of mice with 250 mg/kg/day produces a 1.8 fold increase in activity of glutathione S-transferase 6 , whereas treatment with 1 g/kg produces a 20% decrease in glutathione S-transferase activity 7, 8 . Curcumin can act as an antioxidant or prooxidant, depending on dose. At 10 µM (the maximum dose used in the present study), curcumin is a documented antioxidant 9 . At 50 µM, it generates superoxide radicals and induces apoptosis 10 . Reactive oxygen species may be necessary for curcumin’s apoptotic effect 10 .
Correspondence re: Somasundaram et al., Dietary Curcumin Inhibits Chemotherapy-induced Apoptosis in Models of Human Breast Cancer. Cancer Research 63, 5165-5167, August 15, 2003
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A study on colon cancer cells found a possible contra-indication between N-acetyl-cysteine and curcumin, noting that N-acetyl-cysteine inhibited the expression of the GADD153 protein, which was thought responsible for curcumin’s apoptotic effects. Upregulation of GADD153 “preceded the appearance of recognizable features of apoptosis in curcumin-treated HCT-116 colonocytes.”
The study could not conclude that the antioxidant effect of NAC was behind the inhibition of GADD153, because neither catalase nor vitamin E prevented the curcumin-induced upregulation. So “the involvement of reactive oxygen species … remains somewhat unclear.” The corollary made was that perhaps it is the upregulation of glutathione, which NAC is known to produce, that caused the GADD153 inhibition 6.