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Doxorubicin and 5-fluorouracil resistant hepatic cancer cells demonstrate stem-like properties

  • Method in Cell Science
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Abstract

The efficacy of hepatocellular carcinoma (HCC) treatment is very low because of the high percentage of recurrence and resistance to anticancer agents. Hepatic cancer stem cells (HCSCs) are considered the origin of such recurrence and resistance. Our aim was to evaluate the stemness of doxorubicin and 5-fluorouracil resistant hepatic cancer cells and establish the new method to isolate the HCSCs from primary cultured HCC tumors. HCC biopsies were used to establish primary cultures. Then, primary cells were selected for HCSCs by culture in medium supplemented with doxorubicin (0, 0.1, 0.25, 0.5 or 1 μg/mL), 5-fluorouracil (0, 0.1, 0.25, 0.5 or 1 μg/mL) or their combination. Selection was confirmed by detection of HCSC markers such as CD133, CD13, CD90, and the side population was identified by rhodamine 123 efflux. The cell population with the strongest expression of these markers was used to evaluate the cell cycle, gene expression profile, tumor sphere formation, marker protein expression, and in vivo tumorigenesis. Selective culture of primary cells in medium supplemented with 0.5 μg/mL doxorubicin and 1 μg/mL 5-fluorouracil selected cancer cells with the highest stemness properties. Selected cells strongly expressed CD13, CD133, CD90, and CD326, efflux rhodamine 123 and formed tumor spheres in suspension. Moreover, selected cells were induced to differentiate into cells with high expression of CD19 and AFP (alpha-fetoprotein), and importantly, could form tumors in NOD/SCID mice upon injection of 1 × 105 cells/mouse. Selective culture with doxorubicin and 5-fluorouracil will enrich HCSCs, is an easy method to obtain HCSCs that can be used to develop better therapeutic strategies for patients with HCC, and particularly HCSC-targeting therapy.

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Abbreviations

5-FU:

5-Fluorouracil

AFP:

Alpha-fetoprotein

CD:

Cluster of differentiation

Dox :

Doxorubicin

EpCAM:

Epithelial cell adhesion molecule

HCC:

Hepatocellular carcinoma

HCSCs:

Hepatic cancer stem cells

HE:

Haematoxylin and Eosin

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  1. Laboratory of Stem Cell Research and Application, University of Science, VNU-HCM, HCM City, Vietnam

    Ngoc Bich Vu, Tam Thanh Nguyen, Ngoc Kim Phan & Phuc Van Pham

  2. University of Medical Center, Ho Chi Minh University of Medicine and Pharmacy, HCM City, Vietnam

    Long Cong-Duy Tran, Cong Dinh Do & Bac Hoang Nguyen

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  1. Ngoc Bich Vu
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  2. Tam Thanh Nguyen
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  3. Long Cong-Duy Tran
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  4. Cong Dinh Do
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  5. Bac Hoang Nguyen
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  6. Ngoc Kim Phan
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  7. Phuc Van Pham
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Correspondence to Phuc Van Pham.

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Vu, N.B., Nguyen, T.T., Tran, L.CD. et al. Doxorubicin and 5-fluorouracil resistant hepatic cancer cells demonstrate stem-like properties. Cytotechnology 65, 491–503 (2013). https://doi.org/10.1007/s10616-012-9511-9

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  • DOI: https://doi.org/10.1007/s10616-012-9511-9

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