Charlotta D. Mock
,
Brian C. Jordan
and
Chelliah Selvam
*
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX-77004, USA. E-mail: chelliahs@tsu.edu
First published on 2nd September 2015
More than 230000 diagnosed cases of invasive breast cancer in women were estimated in 2014 and an expected 40000 deaths attributed to the aggressive carcinoma. An effective approach to diminish the morbidity and mortality of breast cancer is the development of chemopreventive and chemotherapeutic agents. Nutraceuticals have demonstrated their ability to proficiently halt carcinogenesis. The administration of natural compounds able to effectively serve as chemoprevention and chemotherapeutics without causing harm or adverse effects is imperative. Curcumin derived from the rhizome of Curcuma longa L., is a common spice of India, used for centuries because of its medicinal properties. The main component of curcumin possesses a wide range of biological activities; anti-proliferative, anti-inflammatory, and apoptotic characteristics modulated through the inactivation of pathways such as EGK and Akt/mTOR. In addition, curcumin alters the expression of cytokines, transcription factors, and enzymes involved in cell vitality. The in vivo application of curcumin in breast cancer is hindered by its limited bioavailabiity. The synthesis of curcumin analogues and delivery via nanoparticles has demonstrated enhanced bioavailability of curcumin in the malignancy. This review focuses on recent developments in the use of curcumin, curcumin analogues, and novel delivery systems as a preventive and therapeutic method for breast cancer.
The classification of breast cancer is based upon its wide array of unique biological markers and signalling pathways. Targeted therapeutic approaches focus on proteins and pathways such as MAPK, HER2/EKBB2, p13K/Akt/mTOR, PAPP, TGF-α, EGF, and p53 identified in the malignancy.5,6 Terlikowska et al.7 have identified approximately twenty-six curcumin mediated signalling pathways such as PPAR, COX-2, EGFR and NF-κB. In vivo studies are often performed in three established adenocarcinoma and invasive ductal carcinoma cell lines; MDA-MB-231, MDA-MB-468, SkBr3 and MDA-MB-435, MCF-7, T47D respectively.8
In 2003, 70% of new drugs developed were derived from natural compounds. During the years 1983 through 1994 more than 62% of approved therapies for cancer were designed from natural products or their analogues.9 The most effective method to combat cancer with natural compounds is to implement an attractive strategy that will target pathways and enzymes leading to anti-proliferation and cytotoxicity. The therapeutic design should also effectively minimize or halt the carcinogenesis and increase cytoprotectivity of healthy cells and organs. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a polyphenolic compound isolated from Curcuma longa, that has demonstrated a wide range of biological activities; anti-inflammatory,10–14 anti-oxidative,15–19 antibacterial,20–26 rheumatoid arthritis,12,27–33 Alzheimer's,34–42 psoriasis,43,44 and diabetes.45–53 Curcumin has been investigated for its anti-cancer properties for cancers such as lung,54–58 ovarian,59–65 colorectal,66–73 and pancreatic.74–81
Therapeutic applications of curcumin are limited because of its reduced bioavailability.82 The polyphenolic compound, curcumin is only slightly soluble in an aqueous environment, experiences degradation at alkaline pH, rapidly metabolized and conjugated in the liver (curcumin sulfate and curcumin glucuronide), undergoes rapid systemic elimination, is excreted in feces, demonstrates poor tissue absorption, and characterized as a Class II drug.83–85 In vitro application as a pharmaceutical agent is challenged by curcumin's degradation and in vivo administration results in decreased efficacy because of metabolic changes.86 Enhancement of curcumin's activity and bioavailability can be achieved through modifications of its chemical structure. Curcumin binds to various biological enzymes/proteins such as COX1 and COX2, TNF-α, MMP3 and MMP13, tyrosine kinase, protein kinase c (PKC), and reductases such as thioredozin reductase.
Biological effects | Curcumin (conc.) | Mechanism of action | Cell line | Ref. |
---|---|---|---|---|
Curcumin inhibits cell migration and invasion via TGF-B/Smad pathway in breast cancer cells | (5–50 μM) | ↓MMP-9 | MDA-MB-231 | 90 |
↓TGF-β1 | ||||
↓ERK 1/2 | ||||
↓p38MAPK | ||||
Curcumin inhibits MMP gene expression activity in breast cancer cells | (10–40 μm) | ↓MMP-2 & 9 | MDA-MB-231 | 91 |
↑TIMP 1 & 4 | ||||
Curcumin inhibits cell proliferation in triple negative breast cancer cells via EGFR-MAPK signalling pathway | (10–30 μM) | ↓pERK 1/2 | MDA-MB-231 | 92 |
↓PEGFR | ||||
Curcumin inhibits gene expression in breast cancer cells and identifies relevant networks involved in cell growth and development | 20 μM | ↓Cell viability | MDA-MB-231 | 93 |
↓EGR1 gene expression | ||||
Curcumin enhance tumour suppression proteins and inhibits pro-carcinogenic expression in breast cancer cells | (10 μM) | ↑p16,21,53 | MDA-MB-231 | 94 |
↓MMP-2 | ||||
↓MMP-9 | ||||
↓SDF-1 | ||||
↓IL-6 | ||||
Curcumin induces apoptosis and enhances sensitivity to tamoxifen in breast cancer cells | 10–30 μM | ↓Bcl-2 | MCF-7/LCC2 | 95 |
↓Bcl-XL | MCF-7/LCC9 | |||
↓IKK | ||||
↓NF-KB | ||||
↓Akt/mTOR | ||||
Curcumin alone or in combination with bisphenol A enhances anti-proliferative activity in breast cancer cells | 1 μM | ↓P53 | MCF-7 | 96 |
↓miR-19a | MDA-MB-231 | |||
↓miR-19b | ||||
↓Cell growth | ||||
Curcumin enhances anti-proliferation via altered expression and activity of proteins in breast cancer cells | 10–30 μM | ↓Fen1 | MCF-7 | 97 |
↓Cell proliferation | ||||
Curcumin alters Akt/SKP2 signalling pathway in breast cancer cells for anti-proliferative activity | 2–40 μM | ↓SKP2 | MCF-7 | 98 |
↓Akt phosphorylation | MDA-MB-231 | |||
Curcumin inhibits EMT expression with LPS in breast cancer cells | 20–70 μM | ↓Cell invasion | MCF-7 | 99 |
↓NF-KB activation | MDA-MB-231 | |||
↓Cell proliferation | ||||
↑E-cadherin | ||||
↓Vinmentin | ||||
Curcumin inhibits triclocarban cytotoxicity in breast cancer cells | 10–20 μM | ↓Cell viability | MCF10A | 100 |
↑ROS | MCF-7 | |||
↑DNA damage | ||||
↓ERK-NoX | ||||
Curcumin inhibits expression of TNF-α, induces aerobic glycolysis and mitochondrial metabolism in breast cancer cells | 5–10 μM | ↑PGC1 | MCF10A | 101 |
↓GLUT1 RNA expression | MCF-7 | |||
Curcumin inhibits FABP5 expression in triple negative breast cancer cells by enhancing sensitivity to retinoic acid | 30–50 μM | ↓Cell proliferation | MDA-MB-231 | 102 |
↓PPAR β/Δexpression | MDA-MB-468 | |||
Curcumin induces apoptotic proteins to restore sensitivity to TRAIL in breast cancer cells | 20 μM | ↑ROS | MCF-7 | 103 |
↑TRAIL receptor | T47D | |||
↑Cellular caspase activity (Cas 8,3,7) | SK-Br3 | |||
↓IAP (inhibitsor apoptosis protease) | ||||
Curcumin reduces metastatic activity in estrogen receptor negative breast cancer cells | 1–40 μM | ↓Adhesion propensity | SK-Br3 | 104 |
↑Cell death | MDA-MB-231 | |||
MDA-MB-468 |
Jiang et al.,95 performed a study to discover the mechanisms responsible for curcumin's cytotoxicity. The study investigated curcumin's ability to resensitize anti-estrogen-resistant MCF-7/LCC2 and MCF-7/LCC9 breast cancer cell lines to tamoxifen. It was revealed that curcumin induces cell cycle arrest at G2/M and the inactivation of NF-κB and Akt/mTOR signalling pathways, possesses anti-proliferative and pro-apoptotic characteristics, and down regulates EZH2 proteins. The modulation of miR-19/PTEN/Akt p53 pathway by curcumin leads to anti-proliferation of MCF-7 cancer cells exposed to Bisphenol A (BPA), an endocrine disrupter that increases cell proliferation.96 The downregulation of Flap Endonuclease 1 (Fen1) expression is mediated by Nrf2 in an anti-proliferation pathway in the MCF-7 cell line.97
MCF-7 and MDA-MB-231 breast cancer cells respond differently to curcumin. There is a significant deregulated expression of SKP2 in curcumin sensitive MDA-MB-231 cells. The suppression of SKP2 in the MCF-7 cell line occurs at higher concentrations and extended incubations (30 or 40 μM/12 or 24 h). Curcumin inhibits the phosphorylation of Akt at SER-473 in MDA-MB-231 cell lines. However, curcumin treatment in MCF-7 cells results in a substantial increase in Akt phosphorylation. There is a difference in the function of the p13k/Akt-SKP2 pathway of the two cell lines in response to curcumin, highlighting the differential susceptibility of the breast cancer cells to curcumin's cytotoxic effects.98 A study of the effectiveness of curcumin's anti-invasive ability to inhibit morphological changes triggered by lipolysaccharide (LPS) in MCF-7 and MDA-MB-231 cells revealed NF-κB-Snail pathway inactivation mediates suppression and increase of LPS-induced EMT markers vimentin and E-cadherin respectively.99 Sood et al.,100 performed an investigation of human breast cell carcinogenesis induced by triclocarban (TCC) and the use of curcumin as a preventive agent in MCF10A and MCF-7 breast cancer cell lines. TCC, an antimicrobial component in household and personal care products, has the ability to induce progressive human breast cancer carcinogenesis in non-cancerous breast cells to a pre-malignant stage. A significant decrease in cell viability was observed at 10 and 20 μM curcumin concentrations. Curcumin also demonstrated decreases in Erk-Nox pathway activation and ROS accumulation. The administration of curcumin as a preventive therapeutic agent suggests its ability to effectively suppress sporadic breast cancer induced by TCC exposure.
Vaughan et al.,101 investigated the ability of curcumin to reverse altered energy homeostasis of cancer, aerobic glycolysis and mitochondrial metabolism in breast epithelial cell lines MCF-10A and MCF-7. The study concluded curcumin can prevent reduction in mitochondrial cell content that is induced by TNF-α in a dose dependent manner. Curcumin is able to restore retinoic acid (RA) sensitivity to RA-resistant TNBC cells MDA-MB-231, MDA-MB-468, SkBr3, and MCF-7. Curcumin modulates the inhibition of growth in the breast cancer cell lines through the suppression of FABP5/PPARβ/δ pathway.102 An investigation of curcumin's role in the enhancement of TNF-related apoptosis ligand (TRAIL) activity in MCF-7, SKBR3, and T47D breast cancer cell lines revealed a curcumin-TRAIL synergistic relationship that selectively suppresses TRAIL resistance based on the breast cancer cell line. The combination induces down regulation of IAP proteins and induces ROS production leading to enhancement of the mobilization of DR5.103 A time and dose response observation of the metastatic characteristics of estrogen receptor negative cell lines SK-BR3, MDA-MB-231, and MDA-MB-468 in the presence of curcumin concluded the reduction of circulating tumor cells (CTCs) may lower or prevent metastasis. The dose response study observed the effects of curcumin at 24, 48, and 72 h demonstrating a 40 and 47% decrease in adhesion propensity for SKBr3 and MDA-MB-231. A curcumin concentration of 10 μM and 24 h incubation yielded a 20% increase in rolling velocity for all three cell lines.104
Breast cancer studies exploring curcumin's anticancer activities have reported varied signalling pathways and molecular targets in the compound's mechanism of action; enhanced TRAIL activity, induction of cell cycle arrest at the G2/M phase, apoptosis, E-cadherin, ROS accumulation, p16, p21, and p53, caspase 8, 3, & 7, and PGC1, the upregulation of TIMP 1 & 4 expression, downregulation of Flap Endonuclease 1 (Fen1), SKP2 expression and inhibition of cell proliferation, MMP2, MMp9, NF-κB, TGF-β1, ERK 1/2, P38 MAPK, PERK 1/2, PEGFR, EGFR signaling pathway, EGR1 gene expression, SKP2, vinmentin, eRK-Nox, JAK2/STAT3 and Akt/mTOR pathway inactivation, and suppression of FABP5/PPARβ/δ pathway.
Biological effects (chemical structure description) | Curcumin analogue (conc.) | Mechanism of action | Cell line | Ref. |
---|---|---|---|---|
DMC inhibits eukaryotic initiation factor and mRNA translation in breast cancer cells (curcumin without one methoxyl group) | DMC (20 μM) | ↓Cell proliferation | MDA-MB-231 | 106 |
↓FASN expression | ||||
↑AMPK activity | ||||
↓Acetyl CoA carboxlase | ||||
BDMC induces apoptosis in MCF cells by mitochondrial membrane potential and ROS alteration (curcumin without two methoxyl groups) | Bisdemethoxy curcumin (10–40 μm) | ↓Cell proliferation | MCF-7 | 107 |
↑ROS | ||||
↓G2/M phase | ||||
Curcumin analogue BDMC-A inhibits cyclin D1 protein expression in breast cancer cells (positional isomer of BDMC) | BDMC-A (15–75 μM) | ↓Cell viability | MCF-7 | 108 |
Curcumin analogue bis-demethoxy curcumin has an increased efficacy in apoptosis and induction compared to free curcumin (positional isomer of BDMC) | BDMC-A (15 μM) | Regulates P13k/Akt | MCF-7 | 109 |
Apoptotic intrinsic and extrinsic pathways | ||||
↑p53 ↑Bax | ||||
↑Cytochrome C | ||||
↑Apoptosis | ||||
Tetrahydrocurcumin induces intrinsic apoptotic pathway change in breast cancer cells (saturated curcumin analogue) | THC (34–112.5 μM) | ↓Bcl-2 | MCF-7 | 110 |
↑Bax | ||||
↑Cytochrome C | ||||
↑G2/M phase | ||||
↑Apoptosis | ||||
Curcumin analogue RL66 induces cytotoxic effects in ER-negative breast cancer cells (synthetic analogue/N-methyl piperidone analogue) | RL66 (12.6 μM) | ↓HER2/neu expression | MDA-MB-231 | 111 |
↓pAKt/Akt | MDA-MB-468 | |||
SKBr-3 | ||||
Curcumin and its novel analogue PGV-0 and PGV-1 induces cytotoxicity in breast cancer cells resistant to doxorubicin (cyclopentanone) | PGV-0 and PGV-1 (21–82 μM) | ↓p65 | MCF-7 | 112 |
↑G-1 population | ||||
↑Sub-G-1 population | ||||
Curcumin analogue GO-Y030 reduces cell viability and induces apoptosis in breast cancer cells (semi-synthetic analogue) | GO-Y030 (0.5–5.0 μM) | ↓pSTAT3 cell | MDA-MB-231 | 113 |
↑Apoptosis | ||||
↓Cell viability | ||||
Curcumin analogue, PAC inhibits mitochondrial pathway in breast cancer cells (synthetic analogue/N-methyl piperidone analogue) | PAC (10–40 μM) | ↓Bax and Bcl-2 | MCF-7 | 114 |
↓NF-κB | MDA-MB-231 | |||
↑P21waf1 | ||||
↑Th2 production | ||||
IL-4 and IL-10 | ||||
↓Survivin and cyclin D1 |
The results of the study concluded DMC as the most cytotoxic against MDA-MB-231 cells and potent cell proliferation suppression of TNBC cells. BDMC has demonstrated potent inhibition of cell proliferation and vitality by the induction of ROS accumulation.107 Kumaravel et al.,108 performed a comparative study of curcumin and curcumin analogue BDMC-A (an analogue with greater aqueous solubility) which revealed the analogue's cytotoxic and antiproliferative properties are similar to curcumin. Like curcumin, BDMC-A induces cell cycle arrest at the G2/M phase and inhibits the expression of cyclin D. Another study of BDMC-A conducted in vitro observed the induction of apoptosis in MCF-7 breast cancer cells. It was determined that BDMC-A's potency is attributed to the ortho-hydroxy group present. In addition, its effectiveness in the induction of apoptosis occurs by both intrinsic and extrinsic pathways.109
Tetrahydrocurcumin, a Phase I metabolite of curcumin, effectively induces G2/M cell cycle arrest and apoptosis as well as induces antitumor activities via the p38 MAPK pathway when co-administered with SB203580.110 RL66, 1-methyl-3,5-bis[((E)-4-pyridyl)methylidene]-4-piperidone, a second generation curcumin analogue, has high levels of cytotoxicity for ER negative breast cancer cells SKBr3, MDA-MB-231, and MDA-MB-468 both in vivo and in vitro. In vitro studies revealed the induction of apoptosis, cell cycle arrest, JNK 1/2 and MAPK p38 as well as suppression in Akt and HER2 phosphorylation in a mouse xenograft tumor growth model.111 The co-therapeutic potential of curcumin analogues PGV-0 and PGV-1 administered with doxorubicin on MCF-7 and MCF-7/Dox cells has demonstrated PGV-1 enhances the cytotoxic effect of doxorubicin. PGV-1 and curcumin inhibit HER2 and NFκB activation (Fig. 2).112
Hutzen and team synthesized GO-Y030, an active agent in the suppression of cell growth at a magnitude 8 to 40 times greater than free curcumin while still able to retain a similar safety profile. The analogue efficiently induces apoptosis, decreases cell viability, inhibits STAT3 and cell colony formation in MDA-MB-231.113 Al-Hujaily et al.114 compared the bioavailability and distribution of curcumin and 5-bis(4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperdione (PAC) in vitro and in a nude mouse model. The study revealed PAC upregulates p21WAF1, is more efficient than curcumin in apoptosis induction and as an inhibitor of cell survival, NF-κB, cyclin D1, and Bcl-2. In vivo analogue observations revealed better bioavailability and distribution.
Curcumin analogues (natural, semi-synthetic, and synthetic) DMC, BDMC, BDMC-A, RL66, PAC, PGV-1, and GO-Y030 have displayed cytotoxicity, apotototic, anti-proliferative, arrest of the cell cycle, p53, p21waf1, cytochrome C and ROS accumulation induction, upregulation of AMPK activity and the reduction of FASN expression, Bcl-2, NF-κB, survivin, cyclin D1, HER2, acetyl CoA carboxylase, PSTAT3, and PAKt/Akt and pathway activity.
Biological effects | Synergistic agent (curcumin conc.) | Mechanism of action | Cell line | Ref. |
---|---|---|---|---|
Curcumin in combination with docosahexaenoic acid inhibits “PAM5O” genes in in vivo model of DMBA-induced mice | Docosahexanoic acid (DHA) (2 g kg−1) | ↑Maspin expression | SkBr3 ER(-) | 115 |
↓Survivin expression | HER-2+ | |||
↓Tumor progression | In vivo model | |||
↓Tumor initiation | ||||
Curcumin, alone or in combination with silibinin inhibits reverse transcriptase activity in breast cancer cells | Silibinin (5–17.5 μM) | ↓hTERT expression | T47D | 88 |
Curcumin, alone or in combination with docetaxel inhibits relative metabolic activity in breast cancer cells | Docetaxel (28–70 μM) | ↑Total glutathione | MCF-7 | 116 |
MDA-MB-231 | ||||
Curcumin, alone or in combination with resveratrol in immunoliposome inhibits HER2 expression | Resveratrol (0.10–0.02 mM) | ↑Cytotoxicity | JIMT1 | 117 |
MCF-7 | ||||
Curcumin, alone or in combination with paclitaxel enhances apoptosis in breast cancer cells | Paclitaxel (12.6 μM) | ↑Bax expression | MCF-7 | 118 |
↑EGFR signal blockade | ||||
↓Bcl2 expression | ||||
Curcumin combined with silibinin inhibits leptin receptor in breast cancer cells | Silibinin (20–120 μM) | ↓Leptin secretion | T47D | 119 |
Curcumin, alone or in combination with 5-FU enhances cytotoxicity in breast cancer cells | 5-Fuorouracil (5-FU) (10 μM) | ↓DNA synthesis | MDA-MB-231 | 120 |
Curcumin and mitomycin C (MMC) synergistically inhibits tumour growth and induces apoptosis in breast cancer cells. | 100 mg kg−1 Cur 1.5 mg kg−1 MMC (0.5–5.0 μM) | ↓Tumor growth (MCF-7) | MDA-MB-231 | 121 |
↑Tumorcidal effect | MCF-7 | |||
↑Apoptosis (MDA-MB-231) | ||||
Curcumin combined with carnosol increases anti-proliferative activity in breast cancer cells | Carnosol | ↓Cell vitality | MDA-MB-231 | 122 |
The in vitro analysis of SkBr3 (ER+/HER-2+) breast cancer cells treated with a combination of DHA and curcumin demonstrated an alteration in “PAM50” genes. The in vivo study of induced DMBA breast cancer cells in SENCAR mice revealed the synergistic combination effective in decreasing the incidence of breast cancer, decreased tumor growth progression, decreased expression of survivin and increased expression of maspin. A combination of curcumin with silibinin (milk thistle) has greater effectiveness in cytotoxicity and reduction of cell viability than when curcumin is administered alone. The combination inhibits reverse transcriptase and has cytotoxic effects in T47D cells in a time and dose dependent manner.88 Curcumin, alone or in combination with docetaxel modifies metabolic properties such as glutathione and lipid/phospholipid metabolism and glucose utilization in MCF7 and MDA-MB-231 breast cancer cells.116 Catania et al.117 conducted a comparison of the effectiveness of free curcumin, liposome loaded with curcumin, and immunoliposome loaded with curcumin bearing herceptin, a HER2 antibody, on JIMT1 and MCF-7 breast cancer cell lines. Greater cytotoxic activities were observed in JIMT1 cells. A decrease in IC50 values of 50–33% versus free curcumin was recorded and the immunoliposome decreased the value further than the curcumin loaded liposome. When curcumin was combined with resveratrol and loaded into an immunoliposome, the nano-formulation exhibited improved efficacy in the HER2 positive JIMT1 cell line by 7% and IC50 decrease compared to the liposome form. Paclitaxel, a traditional anti-cancer drug, administered with curcumin has shown a synergistic inhibitory effect in MCF-7 breast cancer cells and female Kunming mouse model. The combination results in an increase of anti-proliferation, apoptosis, and Bax expression in vitro. A reduction in the EGFR signalling blockade and a decrease in Bcl-2 expression in MCF-7 breast cancer cell line are modulated by the paclitaxel–curcumin combination. The synergistic combination also demonstrates an increase in anti-tumour efficacy in the in vivo model.118 Newjati-Koshki et al.,119 created a curcumin–silibinin combination that demonstrated an ability to inhibit the growth of T47D cells in a dose dependent manner as well as an inhibition of leptin expression and secretion. The ability of 5-fluorouracil (5-FU) to effectively initiate apoptosis and inhibit cancer cell growth is modulated by direct targeting of thymidylate synthase (TS). Overexpression of TS leads to 5-FU resistance in cancerous cells. The administration of curcumin chemosensitizes SKBR3, MCF-7, and MDA-MB-231 breast cancer cells that demonstrated 5-FU resistance. The co-administration of 5-FU and curcumin results in inhibition of DNA synthesis in MDA-MB-231 cells and enhanced LD50.120 A synergistic administration of EGCG and curcumin results in inhibition on cell growth and induced apoptosis in MCF-7 cells that are both doxorubicin (DOX) sensitive and resistant. Qian-Mei et al.,121 studied the combination of curcumin and mitomycin C (MMC) on a MCF-7 xenograft mouse model and observed an increase in apoptosis and inhibition of tumour growth via the ERK pathway. The group also recognized the alteration of more than twenty signalling pathways of twenty-five expressed genes. Curcumin administered with carnosol in SKOV-3 and MDA-MB-231 cell lines results in a synergistic reduction of cell vitality and increased anti-proliferation.122
Synergistic relationships of curcumin with established therapeutic agents used in the treatment of breast cancer have demonstrated enhanced efficacy. Curcumin administered with agents such as docosahexaneoic acid, silibinin, docetaxel, resveratrol, paclitaxel, 5-FU, mitomycin C, and carnosol have yielded promising results in the induction in cytotoxicity, apoptosis, Bax and maspin expression, EGFR signaling blockade activity, and tumorciadal effects, and the reduction of tumor initiation, growth, and progression, Bcl2, survivin and hTERT expression, leptin secretion, cell vitality, and DNA synthesis.
Biological effects | Delivery vessel (curcumin conc.) | Mechanism of action | Cell line | Ref. |
---|---|---|---|---|
Curcumin in a solid lipid nanoparticle enhances cytotoxicity and apoptosis in breast cancer cells | Transferrin-mediated solid lipid nanoparticles (Tf-C-SLN) | ↑Cellular uptake | MCF-7 | 124 |
↓Cell viability | ||||
↑ROS | ||||
Curcumin analogue DAC with β-casein enhances anti-tumour activity in breast cancer cells | Diacetlycurcumin (DAC) (10–40 μM) | ↑Bioavailability | MCF-7 | 125 |
↑Solubility | ||||
↑Cytotoxicity | ||||
↓Cell survival | ||||
Bis-demethoxy curcumin analogue nanoparticles enhance cell cycle arrest and increase apoptosis in breast cancer cells | Bis-demethoxy curcumin analogue nanoparticle (BDMCA-NP) | Fragmentation of PARP and Bax proteins | MCF-7 | 126 |
↑Apoptosis | ||||
↑Dispensability | ||||
↑Surface volume ratio | ||||
BDMC-A in chitosan-starch nanocomposite enhances drug delivery system and cytotoxicity in breast cancer cells | Bis-demethoxy curcumin analogue nanoparticle (BDMCA-CS) (1.953–1000 μg ml−1) | Very slow, sustained & diffused controlled release | MCF-7 | 127 |
↑Cell aggregation | ||||
↑Membrane shrinkage | ||||
Curcumin in PLGA encapsulation induces cytotoxicity by G2/M cell cycle arrest in breast cancer cells | Poly(lactic-co-glycolic acid) (100 μM) | Release by Fickian-law diffusion over 10 days | MCF-7 | 128 |
Increases curcumin intracellularly | ||||
Improves pharmacokinetics and pharmacodynamics | ||||
Curcumin by solid core/mesoporous shell synthesis enhances cellular uptake and cytotoxicity in breast cancer cells | PSS nanocapsules (10–140 pg) | ↓Cell proliferation | MCF-7 | 129 |
Curcumin loaded β-cyclodextrin nanoparticle inhibits telomerase expression | β-Cyclodextrin-curcumin (CD-CUR) 5–100 μM | ↓Telomerase expression | T47D | 130 |
Curcumin PLGA nanoparticle accumulated in breast cancer cells inhibits cell survival and colony formation | Poly(lactic-co-glycolic acid) (10 mg) | 6 fold increase in cellular uptake in metastatic cells | MDA-MB-231 | 131 & 132 |
Sustained curcumin release | ||||
Curcumin halts reattachment of McTNs and decreases metastasis in breast cancer cells | Microtentacles (McTNs) (5–50 μM) | ↓Cellular aggregation | SKBr3 | 133 |
↓Reattachment | MDA-MB-231 | |||
MDA-MB-436 | ||||
MDA-MB-468 | ||||
HMLE | ||||
Bt549 | ||||
HS578 | ||||
Curcumin in CHA nanogel enhances cytotoxicity in drug resistant tumours and breast cancer cells | Cholesteryl-hyaluronic acid (CHA) (28 mg) | High drug load | MDA-MB 231/F | 134 |
Fast penetration | MCF-7 | |||
Sustained drug release | ||||
Significantly increased bioavailability | ||||
Curcumin in polymeric micelles enhances anti-tumour activity in breast cancer models | Curcumin self-assembled polymeric micelles (CUR-M) (15 mg) | Slow and sustained release | 4T1.2 | 135 |
↑Cytotoxicity | ||||
↑Cellular uptake | ||||
Curcumin and S-trans in a PEG nanomicelle synergistically inhibits tumour growth in breast cancer cells | S-trans-farnesylthiosalcycic acid (FTS) (10 μM) | Enhanced in vitro and in vivo anti-tumour activity | 4T1.2 | 136 |
↑Cytotoxicity | ||||
↓Akt | ||||
↓NF-Kb | ||||
Hydrazinocurcumin in nanoparticle inhibits tumour progression in breast cancer model | Legumain-targeting liposomal nanoparticle (Leg-HC-NP) (100 μm) | ↑Tumor sensitivity | 4T1 | 137 |
↓Tumor growth | ||||
↑Apoptosis | ||||
↓Cell proliferation |
Yallapu et al.131 synthesized NANO-Cur6, a curcumin encapsulated PLGA nanoparticle, by using a nano-precipitation technique which resulted in a six-fold cellular uptake and sustained release, decreased cell proliferation, and increased apoptosis in MDA-MB-231 cells. The nanoparticle also has the ability to halt the circulation of MDA-MB-231 cells in the number of adhering tumour cells and vascular adhesion by 70 and 50% respectively.132 Microtentacles (McTNs) are plasma membrane protrusions of tubulin-like material that form detached or suspended cells and assist in cell reattachment. Targeting McTNs containing curcumin leads to rapid elimination of McTN cancer-stem-like cells (CSC) found in MDA-MB-231 and results in the inhibition of cell reattachment.133 Xin Wei et al.134 synthesized cholesteryl-hyaluronic acid (CHA) nanogel conjugates to address CD44 (+) and drug resistant tumours in MDA-MB-231 and MFC-7 breast cancer cell lines. The CHAs displayed fast penetration, high therapeutic activity, sustained drug release, and 2 to 7 times higher cytotoxicity in CD44 (+) breast cancer.
Studies of 4T1.2, an aggressive metastatic breast cancer model, with curcumin encapsulated nanoparticles have revealed enhanced activity. Cur-M, a water based formula, has a slower, sustained release that can last a week, maintains cytotoxicity, effective in tumour growth inhibition, apoptosis, and decreased cell proliferation in a 4T1 breast tumour model.135 Chen et al.136 observed the potent and sustained synergistic inhibition of curcumin and S-trans, trans-farrenslthiosalicyclic acid (FST) in a nanomicelle system on a 4T1.2 cancer mouse model. The nanomicelle demonstrated enhanced anti-tumour activity. Leg-HC-NPs, a legumain-targeting liposomal nanoparticle encapsulated with hydrazinocurcumin, in 4T1 breast cancer cell line and murine mouse model suppresses STAT3 in vitro and induces apoptosis, migration, angiogenesis, tumour growth inhibition, and prolonged life span in vivo.137
Drug delivery studies have identified solid lipid nanoparticles, PLGA encapsulation, microtentacles, nanogels, and polymeric micelles as effective administration techniques to address the pharmacokinetic problems of curcumin/curcumin analogues and improve its anti-cancer activity.
RL66, has demonstrated the ability to suppress tumour volume and weight in a time dependent manner in a xenograft mouse model. When treated with 8.5 mg kg−1 of RL66 for 4 weeks, tumour volume and growth suppression was apparent and continued until the conclusion of the 10 week study.111 Al Hujaily et al.114 investigated the effectiveness of a curcumin analogue, PAC on breast cancer cell line MDA-MB-231 in a nude mouse xenograft model. The 14 day study of 100 mg kg−1 day revealed tumour size reduction, inhibitory effects on onco-proteins, and greater biodistribution and bioavailability than curcumin alone. A synergistic combination of curcumin and docosahexaenoic acid decreased the incidence of and progression of breast tumours as well as reduced the initiation of the tumours in SENCAR mice. Breast tumours were induced in the mouse model by DMBA, a potent carcinogen that affects many sites including the mammary glands. A treatment of 0–20 μM of curcumin and 10–100 μM of DMBA for 133 days showed the synergistic effects of DHA and curcumin were effective on the SK-Br-3 phenotype that possessed ER – and Her-2+ characteristics.115
Zhan et al.118 studied curcumin's ability to potentiate paclitaxel in breast cancer cells. Female Kunming mice with S180 cells transplanted were treated with paclitaxel, curcumin, and paclitaxel–curcumin combination for 10 days at 25–225 mg kg−1 of curcumin and 5 mg kg−1 of paclitaxel. When administered alone, paclitaxel demonstrated significant growth suppression (Table 5).
Compound | Cell line/animal model | Dose/time interval (days) | Biological activity | Ref. |
---|---|---|---|---|
RL66 | MDA-MB-498/CD-1 mice (female) | 8.5 mb kg−1 (70 d) | Decreased tumour volume and weight in time dependent manner | 111 |
Curcumin & DHA | DMBA induced (SK-BR-3 phenotype)/SENCAR mice (female) | 0–20 μM (Cur) 10–100 μM (DHA) (133 d) | Decreased tumour incident and progression and delayed tumour initiation | 114 |
PAC | MDA-MB-231/nude mice | 100 mg kg−1 day−1 (14 d) | Greater biodistribution and bioavailability and decreases tumour size | 115 |
Curcumin & paclitaxel | S180 cell transplant/Kunming mice (female) | 25–225 mg kg−1 (Cur) 5 mg kg−1 (PTX) (10 d) | Marked growth inhibition of tumour in dose-dependent manner | 118 |
Curcumin-micelles | 4T1 T tumor model/BALB/C mice | 30 mg kg−1 (10 d) | Inhibits growth and spontaneous pulmonary metastasis. Improved anti-tumour and anti-metastasis activity | 135 |
PEG-FTS micelles w/curcumin | MCF-7/4T1 tumor model | 12.5–50 μM (4 d) | Improved anti-tumour activity | 136 |
Leg-HC-NPs | 4T1 cells/BALB/C (female) | 1 mM (15 d) | Increased tumour sensitivity and inhibits tumour growth | 137 |
However, the synergistic relationship revealed efficient tumour growth inhibition in a dose-dependent manner. Curcumin loaded, self-assembled polymeric micelles have shown increase in apoptotic cells and significant inhibition of tumour growth and spontaneous pulmonary metastatic in a subcutaneous 4T1 breast tumour model.135 Chen et al.136 investigated the synergistic cytotoxicity of curcumin and FTS in a micellar system targeting breast cancer in 4T1.2 breast cancer model. The study revealed significant efficacy in inhibiting tumour growth without loss of body weight and abnormal appearance. Nanoparticle encapsulation with hydrazinocurcumin has demonstrated tumour weight inhibition and prolonged life span of tumour bearing mice in a 4T1 BALB/c model for 15 days.137
Clinical trials gov. identifier no. | Year started | Phase | Patient condition | Dose of curcumin | Purpose |
---|---|---|---|---|---|
NCT01975363 | 2015 | Pilot/recruiting | Atypical ductal breast hyperplasia | 100 mg d−1 for 3 months | Effect of curcumin nanoemulsion formulation in reducing inflammatory changes in breast tissue in obese women at high risk for breast cancer. |
Phase I complete | 2010 | Completed | Metastatic | 8000 mg d−1 for 18 weeks | Determine optimum dose of docetaxel – curcumin combination |
NCT01740323 | 2015 | Phase II/recruiting | Breast cancer | 600 mg d−1 for 6 weeks | Curcumin vs. placebo for chemotherapy-treated breast cancer patients undergoing radiotherapy |
Delivery systems that encapsulate curcumin in nanoparticles or liposomes represent a viable alternative to oral administration. Nanoparticles and liposomes carriers may be tumour targeted and release curcumin over time while retaining curcumin's efficacy and cytoprotective nature.
This journal is © The Royal Society of Chemistry 2015 |