Abstract
“Combination therapy”, which is a treatment modality combining two or more therapeutic agents, is considered a cornerstone of cancer therapy. The combination of anticancer drugs, of which functions are different from the other, enhances the efficiency compared to the monotherapy because it targets cancer cells in a synergistic or an additive manner. In this study, the combination of paclitaxel and sorafenib in low concentration was evaluated to target cancer stem cells, miPS-BT549cmP and miPS-Huh7cmP cells, developed from mouse induced pluripotent stem cells. The synergistic effect of paclitaxel and sorafenib on cancer stem cells was assessed by the inhibition of proliferation, self-renewal, colony formation, and differentiation. While the IC50 values of paclitaxel and sorafenib were approximately ranging between 250 and 300 nM and between 6.5 and 8 µM, respectively, IC50 of paclitaxel reduced to 20 and 25 nM, which was not toxic in a single dose, in the presence of 1 µM sorafenib, which was not toxic to the cells. Then, the synergistic effect was further assessed for the potential of self-renewal of cancer stem cells by sphere formation ability. As a result, 1 µM of sorafenib significantly enhanced the effect of paclitaxel to suppress the number of spheres. Simultaneously, paclitaxel ranging in 1 to 4 nM significantly suppressed not only the colony formation but also the tube formation of the cancer stem cells in the presence of 1 µM sorafenib. These results suggest the combination therapy of paclitaxel and sorafenib in low doses should be an attractive approach to target cancer stem cells with fewer side effects.
Highlights
Cancer is characterized by unlimited growth ability and usually unaffected by growth-preventing signals from other tissues, which results in invasion to local tissues and metastasis to other organs tissues [1,2]
MiPS-BT549cmP cells [12] and miPS-Huh7cmP cells [14], were obtained by the conversion of miPSCs, in which the puromycin resistant gene and green fluorescent protein (GFP) gene were cloned under the control of the Nanog promoter, in the presence of CM from human breast cancer cell line BT549 cells (ATCC HTB-122) and the human liver cancer cell line Huh7 cell line (Riken Cell Bank)
Experiments were performed in triplicate and data are presented as the mean ± SD of three separate experiments. Both cells exhibited two different sub-populations; one was cells expressing GFP which indicates the presence of cancer stem cells (CSCs) as the original miPSCs contained the resistant gene and (GFP) gene which were cloned under the control of the Nanog promoter, while the second was fibroblast-like cells without expressing GFP
Summary
Cancer is characterized by unlimited growth ability and usually unaffected by growth-preventing signals from other tissues, which results in invasion to local tissues and metastasis to other organs tissues [1,2]. Cancer tissues contain several distinct cellular subpopulations reflecting the heterogeneity arising from a rare population of selected cells [3]. These cells are hypothesized to be cancer stem cells (CSCs) that have tumorgenicity and self-renewal abilities [4,5]. Due to chemo-resistance, chemotherapy usually eliminates the non-CSC population. CSCs, which were in a temporary dormant status, are enriched, resulting in tumor relapse and metastasis. The combination of multiple anticancer agents sometimes allows the reduction of the drug dose, demonstrating higher response rates, superior safety, and efficacy to monotherapies and avoids the evolution of multi-drug resistance to administered drugs
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