Abstract
The precise mechanism about drug resistance of cancer stem cells (CSCs) has not yet been completely understood. Based on the expression of CD44 and CD133, two well-recognized cell surface markers for CSC identification, we tried to separate HCT8 colorectal cancer cells into different subpopulations and then investigated how the expression of CD44 and CD133 associated with doxorubicin (DXR) resistance. Interestingly, DXR resistance was observed in CD44+CD133+ (P < 0.01vs. all other subpopulations), but not in CD44+CD133− cells. CD44+CD133+ cells also showed an enhanced expression of ABCB1 and drug efflux ability (P < 0.001vs. all other subpopulations), but verapamil, an inhibitor of ABCB1, only partially mitigated the DXR resistance. Independent on the accumulation of DXR, lower level of reactive oxygen species and higher expression of Nrf2 were detected in CD44+CD133+ than CD44+CD133− cells (P < 0.05). Unexpectedly, silencing CD133 by siRNA only partially enhanced the cytotoxicity of DXR, but did not obviously change the expression of ABCB1 and the accumulation of DXR in CD44+CD133+ cells. Complex mechanisms, including drug excretion and redox regulation, are likely involved in the DXR resistance of CD133-positive cells, suggesting the difficulty of drug resistance problem in cancer chemotherapy.
Highlights
The heterogeneity of cancer cells is generally accepted, and a stem cell-like subpopulation that is called “cancer stem cells” (CSCs) has been identified in various types of malignant tumors
We further found that the intracellular accumulation of DXR in CD44+CD133+ cells was obviously increased by the treatment with verapamil, an inhibitor for drug efflux cell membrane transporters of ATP-binding cassette subfamilies of B member 1 (ABCB1) and ABCG2 (Figure 2(b))
By using the well-recognized cell surface markers of CD44 and CD133 for CSC identification, we tried to separate the HCT8 human colon cancer cells into CD44, CD44+, CD44+CD133, and CD44+CD133+ subpopulations and investigated how the expressions of CD44 and CD133 associated with drug resistance
Summary
The heterogeneity of cancer cells is generally accepted, and a stem cell-like subpopulation that is called “cancer stem cells” (CSCs) has been identified in various types of malignant tumors. Previous studies have demonstrated that the CD44 is a biomarker and plays critical roles in the maintenance of CSCs, the resistance to various therapies/stresses, and the metastasis of cancer cells [5,6,7,8,9,10,11]. CD133 is originally identified as protein expressing on the cell surface of hematopoietic stem cells [12] and has subsequently been found to be critical in the maintenance of “stemness” of stem cells in various tissues [13,14,15,16,17,18]. Stem Cells International that the expression of CD133, rather than CD44, closely associated with doxorubicin (DXR) resistance, at least partially through drug excretion and redox regulation
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