HER2 Support Group Forums - View Single Post - Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cel

Rich66 · 11-10-2009, 05:26 PM

NOTE: THIS RESEARCHER SAYS CURCUMIN MAY CONFLICT WITH CHEMO (!?)

Breast Cancer Res Treat. 2009 Nov 7. [Epub ahead of print]
Targeting breast stem cells with the cancer preventive compounds curcumin and piperine.
Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS.

Division of Hematology/Oncology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, 2150 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI, USA, mkakaral@umich.edu.
The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 muM and completely at 10 muM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 muM and completely at 10 muM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials.

PMID: 19898931

Mol Carcinog. 2009 Dec 18. [Epub ahead of print]
Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells.

Elamin MH, Shinwari Z, Hendrayani SF, Al-Hindi H, Al-Shail E, Khafaga Y, Al-Kofide A, Aboussekhra A.
Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G(2)/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of beta-catenin, the activate/phosphorylated form of Akt and NF-kappaB, which led to downregulating the three common key effectors, namely C-myc, N-myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl-2, a downstream anti-apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl-2, were sensitized to curcumin by the addition of the Shh antogonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and gamma-rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl-2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh-targeted therapy for medulloblastomas. (c) 2009 Wiley-Liss, Inc.

PMID: 20025076 [PubMed - as supplied by publisher]

Related cancer stem cell/Cyclopamine/Hedgehog info HERE

Basic Clin Pharmacol Toxicol. 2007 Dec;101(6):427-33. Epub 2007 Oct 9.
Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells.

Chen Y, Shu W, Chen W, Wu Q, Liu H, Cui G.
Department of Haematology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. yanchen@public.wh.hb.cn
Curcumin, the active chemical of the Asian spice turmeric, exhibits anticancer activity in several human cancer cell lines. We previously have proved that curcumin was a new member of the histone deacetylases (HDAC) inhibitors, while constitutive nuclear factor kappa B (NF-kappaB) is believed to be a crucial event for enhanced proliferation and survival of malignant cells. Here, we investigate the effect of curcumin on the activation of NF-kappaB signal molecule in Raji cells to explore its relationship with HDACs or p300/CREB binding protein (CBP). Curcumin presented striking proliferation inhibition potency on Raji cells in vitro, with the IC(50) value for 24 hr being 25 micromol/l. Significant decreases in the amounts of p300, HDAC1 and HDAC3 were detected after treatment with curcumin. These suppressing effects were more pronounced when the administered dose increased. The protection degradation of HDAC1 and p300 by MG-132 could be partially reversed by curcumin. Furthermore, curcumin could also prevent degradation of I kappaB alpha and inhibit nuclear translocation of the NF-kappaB/p65 subunit, as well as expression of Notch 1, induced by tumour necrosis factor-alpha. The results suggest that the depressive effect of curcumin on NF-kappaB signal transduction pathway may be mediated via the various components of the HDACs and p300/Notch 1 signal molecules, and may represent a new remedy for acute leukaemia.

PMID: 17927689 [PubMed - indexed for MEDLINE]

Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):534-42.
Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity.

Sandur SK, Deorukhkar A, Pandey MK, Pabón AM, Shentu S, Guha S, Aggarwal BB, Krishnan S.
Department of Experimental Therapeutics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
PURPOSE: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. METHODS AND MATERIALS: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-kappaB (NF-kappaB) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. RESULTS: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-kappaB activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-kappaB activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of kappaB alpha, inhibition of inhibitor of kappaB kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-kappaB-regulated gene products (Bcl-2, Bcl-x(L), inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). CONCLUSIONS: Our results suggest that transient inducible NF-kappaB activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy.

PMID: 19735878 [PubMed - indexed for MEDLINE]

11-10-2009, 05:26 PM	#2
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer NOTE: THIS RESEARCHER SAYS CURCUMIN MAY CONFLICT WITH CHEMO (!?) Breast Cancer Res Treat. 2009 Nov 7. [Epub ahead of print] Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS. Division of Hematology/Oncology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, 2150 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI, USA, mkakaral@umich.edu. The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 muM and completely at 10 muM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 muM and completely at 10 muM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials. PMID: 19898931 Mol Carcinog. 2009 Dec 18. [Epub ahead of print] Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. Elamin MH, Shinwari Z, Hendrayani SF, Al-Hindi H, Al-Shail E, Khafaga Y, Al-Kofide A, Aboussekhra A. Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G(2)/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of beta-catenin, the activate/phosphorylated form of Akt and NF-kappaB, which led to downregulating the three common key effectors, namely C-myc, N-myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl-2, a downstream anti-apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl-2, were sensitized to curcumin by the addition of the Shh antogonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and gamma-rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl-2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh-targeted therapy for medulloblastomas. (c) 2009 Wiley-Liss, Inc. PMID: 20025076 [PubMed - as supplied by publisher] Related cancer stem cell/Cyclopamine/Hedgehog info HERE Basic Clin Pharmacol Toxicol. 2007 Dec;101(6):427-33. Epub 2007 Oct 9. Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells. Chen Y, Shu W, Chen W, Wu Q, Liu H, Cui G. Department of Haematology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. yanchen@public.wh.hb.cn Curcumin, the active chemical of the Asian spice turmeric, exhibits anticancer activity in several human cancer cell lines. We previously have proved that curcumin was a new member of the histone deacetylases (HDAC) inhibitors, while constitutive nuclear factor kappa B (NF-kappaB) is believed to be a crucial event for enhanced proliferation and survival of malignant cells. Here, we investigate the effect of curcumin on the activation of NF-kappaB signal molecule in Raji cells to explore its relationship with HDACs or p300/CREB binding protein (CBP). Curcumin presented striking proliferation inhibition potency on Raji cells in vitro, with the IC(50) value for 24 hr being 25 micromol/l. Significant decreases in the amounts of p300, HDAC1 and HDAC3 were detected after treatment with curcumin. These suppressing effects were more pronounced when the administered dose increased. The protection degradation of HDAC1 and p300 by MG-132 could be partially reversed by curcumin. Furthermore, curcumin could also prevent degradation of I kappaB alpha and inhibit nuclear translocation of the NF-kappaB/p65 subunit, as well as expression of Notch 1, induced by tumour necrosis factor-alpha. The results suggest that the depressive effect of curcumin on NF-kappaB signal transduction pathway may be mediated via the various components of the HDACs and p300/Notch 1 signal molecules, and may represent a new remedy for acute leukaemia. PMID: 17927689 [PubMed - indexed for MEDLINE] Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):534-42. Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity. Sandur SK, Deorukhkar A, Pandey MK, Pabón AM, Shentu S, Guha S, Aggarwal BB, Krishnan S. Department of Experimental Therapeutics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA. PURPOSE: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. METHODS AND MATERIALS: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-kappaB (NF-kappaB) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. RESULTS: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-kappaB activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-kappaB activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of kappaB alpha, inhibition of inhibitor of kappaB kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-kappaB-regulated gene products (Bcl-2, Bcl-x(L), inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). CONCLUSIONS: Our results suggest that transient inducible NF-kappaB activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy. PMID: 19735878 [PubMed - indexed for MEDLINE] __________________ Mom's treatment history (link)