|Date: 02-15-2013||HC# 011361-466|
Re: Chemopreventive and Chemotherapeutic Potential of Curcumin
Sinha D, Biswas J, Sung B, Aggarwal BB, Bishayee A. Chemopreventive and chemotherapeutic potential of curcumin in breast cancer. Curr Drug Targets. December 1, 2012;13(14):1799-1819.
Breast cancer can differ in various regions worldwide due to differences in health care or individual reproductive history. Breast cancer advances in four distinct stages ranging from 0 (noninvasive) to 3 (invasive to additional organs other than breast tissue). Treatment for this chronic illness includes radiation, chemotherapy, hormone treatment, and surgery. In patients with more serious or advanced forms of breast cancer, chemotherapy-drug resistance has been reported.
These multidrug resistant (MDR) tumors can be more virulent. Focusing on therapeutic targets for the prevention of this phenomenon is paramount to breast cancer research. Plants have traditionally been a potential reservoir for the discovery of novel drugs. This review discusses the potential of curcumin, a compound found in turmeric (Curcuma longa) rhizome, in treating breast cancer.
The polyphenol curcumin, in addition to being an antioxidant, modulates a variety of molecular signaling pathways, resulting in multiple downstream, cellular effects that have been observed in several studies. It is suggested that this diversity in cellular modification results in the reported inhibition of “initiation, promotion, and progression,” of carcinogenesis by curcumin. In addition, it has been postulated that curcumin may not only potentiate the effects of chemotherapy, but also alleviate the toxic adverse side effects of these therapies. Curcumin is reported to have a robust safety profile; and the reported antioxidant effects are suggested to be due to direct scavenging of reactive oxygen species, as well as the stimulation of endogenous antioxidant defenses.
Curcumin is reported to have low bioavailability as seen through lesser gastrointestinal absorption and metabolism. It is suggested that certain bioactivity of curcumin is due to active metabolites other than the compound itself. A clinical trial reported that daily curcumin doses of 4000 mg, 6000 mg, and 8000 mg resulted in 0.51 ± 0.11 µM, 0.63 ± 0.06 µM, and 1.77 ± 1.87 µM of serum curcumin concentrations, respectively. Detected metabolites included curcumin glucuronide, curcumin sulfates, tetrahydrocurcumin, and hexahydrocurcumin. Bioavailability has been addressed by pairing curcumin with other compounds, such as piperine (found in Piper spp.), as well as using structurally modified or analog forms of curcumin.
In vitro studies with curcumin in breast cancer cell lines have reported antiproliferative bioactivity. For example, curcumin attenuated the expression of genes associated with growth in multiple cell lines. When used in combination with the catechin epigallocatechin-3-gallate (EGCG), a compound found in tea (Camellia sinensis), the G2/M phase of the cell cycle was modulated in a breast cancer cell line. Several signaling proteins were also affected. When administered together with docosahexaenoic acid (DHA), curcumin showed antiproliferation in multiple cell lines via stimulatory effects on genes associated with halting the cell cycle, apoptosis, metastasis promotion, and cell adhesion, along with the downregulation of genes active for cancer growth and cell cycle activation. The uptake of curcumin into cells was also promoted when combined with DHA. Curcumin has been found to singly impact the cell cycle in breast cancer cell lines.
Curcumin has been reported to halt cancer cell growth by modulating growth factors in cell lines, as well as other signaling agents. Curcumin has also been shown to attenuate cancer cell adhesion. In addition, curcumin both activated apoptosis and attenuated growth by modifying specific binding proteins in cancer cell lines; the compound also caused damage to cancer cell DNA. In combination with paclitaxel, inhibition of growth and activation of apoptosis was potentiated in certain breast cancer cell lines. When administered with vinblastine, curcumin also showed “additive” impacts.
In vivo, curcumin has shown a variety of anticancer bioactivity specific to breast cancer. For example, curcumin decreased tumors in rats and reduced tumor size both alone and in combination with taxol, in a human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer model. When administered together with mitomycin C (MMC), potentiation of tumor inhibition was observed via impacts on the cell cycle. In vivo, curcumin also halted breast cancer angiogenesis, and in a mouse model of breast cancer, curcumin in combination with paclitaxel potentiated the attenuation of tumor size and proliferation, as well as promoted apoptosis. Curcumin also reduced tumor volume as well as vascular endothelial growth factor receptor 1 (VEGFR-1) when administered in combination with EGCG in mice. In rats, curcumin limited inflammation and decreased adverse side effects common to MMC use.
The limited bioavailability of curcumin has resulted in multiple approaches. In addition to structural modifications or pairing with adjuvants, synthetic analogs of curcumin have been tested for anticancer activity. Various analogs have shown impacts on the cell cycle and apoptosis in vitro, as well as antigrowth and antioxidant properties. The decrease in “tumor burden” in mice was also reported with certain curcumin analogs. Nanocurcumin modifications, such as encapsulating curcumin with various materials, have occasionally resulted in an increase in apoptotic and antigrowth bioactivity in vitro, as well as showing activity against many forms of cancer. Certain formulations have also increased the solubility of curcumin while preserving in vitro anticancer activity.
In terms of clinical trials, curcumin is reported to have a good safety profile; however, clinical trials investigating curcumin for breast cancer are not numerous. [Note: A phase I trial using curcumin in combination with docetaxel for breast cancer is mentioned but not described.] Despite this, it is asserted that natural products may lead to treatment options for breast cancer. Curcumin has shown robust anticancer activity both in vitro and in vivo. In addition, solubility problems may eventually be solved by incorporating analogs or nanotechnology, although detailed safety and efficacy profiles for these compounds or modifications are lacking at present. It is mentioned that overcoming challenges with curcumin metabolism and repeated dosing is necessary for the future of curcumin use in breast cancer treatment. Rigorous clinical trials of curcumin are an ideal future direction for ongoing research of this potential botanical treatment.
—Amy C. Keller, PhD