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Background:
Recent evidence supports the contention that epithelial cancers, including sporadic colorectal cancer (CRC), the incidence
of which increases with aging, are diseases driven by self-renewing cancer stem cells (CSCs). We reported an age-related increase in
colon CSCs. One of the characteristics of CSCs is their resistance to 5-FU based chemotherapy, the mainstay of colon cancer therapeutic
with significant toxicities, resulting in high disease recurrence underscoring the need for improved CSC-targeted non-toxic therapeutics
for CRC. Investigations were carried out to examine the role of CSCs in the development of CRC during aging and to develop therapeutic
strategies using natural agents to combat this malignancy.
Methods:
Both
in vitro
and
in vivo
studies were conducted. Immunohistochemistry and quantitative real-time PCR as well as Western-
blot analysis were used to determine the relative concentration of markers of colon CSCs. Flow cytometry was utilized to examine the
proportion of colon CSCs.
Results:
We found that curcumin, the major active ingredient of turmeric (
Curcuma longa
), used in South Asian cuisine, with no
discernible toxicity synergizes with FOLFOX (5-FU + Oxaliplatin) and attenuates EGFR signaling resulting in inhibition of colon cancer
cell growth. In subsequent studies, we observed that difluorinated curcumin (CDF), a novel analog of curcumin, either alone or together
with FOLFOX markedly stimulates apoptosis of FOLFOX-resistant colon cancer cells and disintegrates colonospheres (surrogate
tumors) that are highly enriched in CSCs. Another approach we utilized was to induce differentiation of colon CSCs by down-regulating
miroRNA-21 (which is upregulated in CRC) and subjecting the differentiated/differentiating cancer cells to CDF either alone or together
with 5-FU based chemotherapy treatment. This approach resulted in a marked attenuation of EGFR signaling, β-catenin/TCF driven
gene transcription and reduction in colon CSCs and cellular growth.
Conclusion:
The conventional 5-FU based chemotherapy together with one of the following agents (a) curcumin, (b) CDF that
eliminates colon CSCs could be effectively utilized for treatment of colorectal cancer. Differentiation of colon CSCs also renders the
chemo-resistant cells highly susceptible to the combination of 5-FU based chemotherapy and CDF.
Biography
Adhip P.N. Majumdar received his Ph.D. degree in Nutrition from London University, London, England in 1968. After 3 years of postdoctoral training
at the Clinical Research Institute of Montreal and at McMaster University, Hamilton, Canada, he joined the Institute of Medical Biochemistry, Aarhus
University, Denmark as a Lecturer in 1972 and subsequently promoted to Senior Lecturer. Dr. Majumdar was awarded the Doctor of Medical Science
(D.Sc.) degree by Aarhus University in 1984. He joined the Veterans Administration Medical Center/Wayne State University, Detroit, U.S.A. in 1986
as an Associate Professor, promoted to the rank of Professor in 1989. He also holds the post of Senior Research Career Scientist at the Veterans
Administration Medical Center.
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