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Cancer
treatment using curcumin derivatives :United
States Patent Application 20060276536
NF-kB (nuclear factor
kappa-light-chain-enhancer of activated B cells) is a protein complex
that controls the transcription of DNA. NF-kB is found in almost all animal
cell types and is involved in cellular responses to stimuli such as stress,
cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial
or viral antigens. Aberrant activation of NF-kB is frequently observed
in many cancers. Moreover, suppression of NF-kB limits the proliferation
of cancer cells. Curcumin blocks activation of NF-kB In addition, curcumin
inhibits the proliferation of a variety of tumor cells and has anti-metastatic
activity.
New York Presbyterian
Hospital and the Weill Medical College
Worldwide clinical trials
have chiseled out a definite place for curcumin in oncology. Among them
are New York Presbyterian Hospital and the Weill Medical College,
which reported that curcumin, a curcuminoid found in turmeric, directly
inhibited the COX-2 enzyme (Zhang et al. 1999). So excited are various
oncologists regarding curcumin that the potent anti-inflammatory has been
classed as a potential third generation cancer chemopreventive agent.
Gastrointestinal
Cancer Research Laboratory/ Charles A. Sammons Cancer Center and Baylor
Research Institute, Baylor University Medical Center, Dallas, Texas,
Various pre clinical cell
culture and animal studies suggest that curcumin has potential as an antiproliferative,
anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance
and radioresistance; as a chemopreventive agent; and as a therapeutic
agent. The spice once relegated to the kitchen shelf, has moved into the
clinic and may prove to be "Curecumin".
University
of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Curcumin (diferuloylmethane)
is a polyphenol derived from the plant Curcuma longa, commonly called turmeric.
Extensive research over the last 50 years has indicated this polyphenol
can
both prevent and treat cancer.
National Research
Laboratory of Molecular Carcinogenesis and Chemoprevention, College of
Pharmacy, Seoul National University, South Korea
Chemoprevention, which is
referred to as the use of nontoxic natural or synthetic chemicals to intervene
in multistage carcinogenesis, has emerged as a promising and pragmatic
medical approach to reduce the risk of cancer. Numerous components of edible
plants, collectively termed "phytochemicals" have been reported to possess
substantial chemopreventive properties. Curcumin, a yellow coloring ingredient
derived from Curcuma longa L. (Zingiberaceae), is one of the most extensively
investigated and well-defined chemopreventive phytochemicals. Curcumin
has been shown to protect against skin, oral, intestinal, and colon carcinogenesis
and also to suppress angiogenesis and metastasis in a variety animal tumor
models. It also inhibits the proliferation of cancer cells by arresting
them in the various phases of the cell cycle and by inducing apoptosis.
Moreover, curcumin has a capability to inhibit carcinogen bioactivation
via suppression of specific cytochrome P450 isozymes, as well as to induce
the activity or expression of phase II carcinogen detoxifying enzymes.
Laboratoire
de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg,
Luxembourg,
Chemoprevention is a promising
anti-cancer approach with reduced secondary effects in comparison to classical
chemotherapy. Curcumin, one of the most studied chemopreventive agents,
is a natural compound extracted from Curcuma longa L. that allows suppression,
retardation or inversion of carcinogenesis. Curcumin is also described
as an anti-tumoral, anti-oxidant and anti-inflammatory agent capable of
inducing apoptosis in numerous cellular systems. In this review, we describe
both properties and mode of action of curcumin on carcinogenesis, gene
expression mechanisms and drug metabolism.
Department of
Radiation Oncology & Biology, University of Oxford, Churchill Hospital,
UK.
Curcumin possesses wide-ranging
anti-inflammatory and anticancer properties. Many of these biological
activities can be attributed to its potent antioxidant capacity at neutral
and acidic pH, its inhibition of cell signaling pathways at multiple levels,
its diverse effects on cellular enzymes, and its effects on cell adhesion
and angiogenesis. In particular, curcumin's ability to alter gene transcription
and induce apoptosis in preclinical models advocates its potential utility
in cancer chemoprevention and chemotherapy. With regard to considerable
public and scientific interest in the use of phytochemicals derived from
dietary components to combat or prevent human cancer, curcumin is currently
a leading agent.
University
of Wisconsin, School of Pharmacy, Madison, WI 53705-2222, USA
The most practical approach
to reduce the morbidity and mortality of cancer is to delay the process
of carcinogenesis through the use of chemopreventive agents. This necessitates
that safer compounds, especially those derived from natural sources must
be critically examined for chemoprevention. A spice common to India and
the surrounding regions, is turmeric, derived from the rhizome of Curcuma
longa. Pre-clinical studies in a variety of cancer cell lines including
breast, cervical, colon, gastric, hepatic, leukemia, oral epithelial, ovarian,
pancreatic, and prostate have consistently shown that curcumin possesses
anti-cancer activity in vitro and in pre-clinical animal models. The
robust activity of curcumin in colorectal cancer has led to five phase
I clinical trials being completed showing the safety and tolerability of
curcumin in colorectal cancer patients. The success of these trials has
led to the development of phase II trials that are currently enrolling
patients. Overwhelming in vitro evidence and completed clinical trials
suggests that curcumin may prove to be useful for the chemoprevention of
colon cancer in humans
Department of
Surgery, Henry Ford Health System, Detroit, MI 48202, USA
Turmeric, the bright yellow
spice extracted from the tuberous rhizome of the plant Curcuma longa, has
been used in traditional Indian and Chinese systems of medicine for centuries
to treat a variety of ailments. Recent evidence that curcumin exhibits
strong anti-inflammatory and antioxidant activities and modulates the expression
of transcription factors, cell cycle proteins, and signal transducing kinases
has prompted the mechanism-based studies on the potential of curcumin
to primarily prevent and treat cancer and inflammatory diseases.
Cullman Laboratory
for Cancer Research, USA
Large bowel cancer is one
of the most common human malignancies in western countries, including North
America. Several epidemiological studies have detected decreases in the
risk of colorectal cancer in individuals who regularly use nonsteroidal
anti-inflammatory drugs (NSAID) like Curcumin. Clinical trials with NSAIDs
in patients with familial adenomatous polyposis have demonstrated that
treatment with NSAIDs causes regression of pre-existing adenomas. Preclinical
efficacy studies using realistic laboratory animal models have provided
scientifically sound evidence as to how NSAIDs act to retard, block, and
reverse colonic carcinogenesis
Centre for
Cellular and Molecular Biology, Uppal Road, Hyderabad, India
Curcumin, a natural component
of the rhizome of curcuma longa has emerged as one of the most powerful
chemopreventive and anticancer agents. Its biological effects range
from antioxidant, anti-inflammatory to inhibition of angiogenesis and is
also shown to possess specific antitumoral activity. The molecular mechanism
of its varied cellular effects has been studied in some details and it
has been shown to have multiple targets and interacting macromolecules
within the cell. Curcumin has been shown to possess anti-angiogenic properties
and the angioinhibitory effects of curcumin manifest due to down regulation
of proangiogenic genes such as VEGF and angiopoitin and a decrease in migration
and invasion of endothelial cells. One of the important factors implicated
in chemoresistance and induced chemosensitivity is NFkB and curcumin has
been shown to down regulate NFkB and inhibit IKB kinase thereby suppressing
proliferation and inducing apoptosis. Cell lines that are resistant to
certain apoptotic inducers and radiation become susceptible to apoptosis
when treated in conjunction with curcumin. Besides this it can also act
as a chemopreventive agent in cancers of colon, stomach and skin by suppressing
colonic aberrant crypt foci formation and DNA adduct formation
Colon Cancer: Curcumin
inhibited chemically induced carcinogenesis in the colon when
administered at different stages of the cancer process. Laboratory rats,
administered
curcumin during either initiation or late in the premalignant phase,
had a lesser incidence and fewer numbers of invasive malignant colon
tumors (Kawamori et al. 1999). Also, by inhibiting COX-2-arachidonic
acid interactions, curcumin suppresses prostaglandins responsible for inflammatory
processes (Plummer et al. 1999). Chronic inflammation has for decades been
regarded as a cause of colon cancer (Konig et al. 1976).
Breast cancer: Curcumin
inhibits the growth of multiple breast cancer cell lines (Inano
et al. 1999), particularly those that result from exposure to environmental
estrogens such as chemicals and pesticides (Verma et al. 1998). Also, curcumin,
estrogen, and estrogen mimickers gain entry into the cell through the aryl
hydrocarbon receptor. Because curcumin competes for entry, it can crowd
out damaging materials (Ciolino et al. 1998). According to researchers,
curcumin blends well with other cancer inhibitors. For example, a curcumin-isoflavonoid
combination suppressed the growth of estrogen receptor-positive cancer
cells up to 95% (Verma et al. 1998).
Skin Cancer:Curcumin
inhibits skin tumors. When applied topically, curcumin reduces
skin inflammation and inhibits local swelling (Huang et al. 1997).
Prostate cancer: Curcumin
was able to decrease the proliferative potential of androgen-independent
prostate cancer cells--and cells of other androgen-dependent
cancers--largely by encouraging apoptosis. Moreover, a significant decrease
in microvessel density, the sustaining blood supply of a tumor, was also
observed (Dorai et al. 2001).
Leukemia: Curcumin-induced
apoptotic cell death in promyelocytic leukemia HL-60 cells at
concentrations as low as 3.5 mcg/mL (Kuo et al. 1996). Protein kinase C
(PKC) and epidermal growth factors (EGF): Curcumin was proclaimed "potentially
useful" in developing anti-proliferative strategies to control tumor growth
by suppressing the activity of protein kinase C (PKC) (Korutla et al. 1995).
As the activity of PKC is slowed down, tumor proliferation is halted (Lin
et al. 1997). PKC transmits signals from the epidermal growth factor receptor
(EGF-R), a cycle that ultimately encourages the growth of tumors. Conversely,
cancers awaiting EGF stimulation are dealt a severe blow if this pathway
is severed. Curcumin blocked the activation of EGF by 90%.
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