Adhip P. N. Majumdar
Wayne State University School of Medicine, USA
Dr. 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, Dr. Majumdar joined the Institute of Medical Biochemistry, Aarhus University, Denmark as a Lecture in 1972, 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 Associated 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.
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, -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.