Combination of SB431542, CHIR99021 and PD0325901 has a synergic effect on abrogating valproic acid‑induced 
epithelial‑mesenchymal transition and stemness in HeLa, 5637 and SCC‑15 cells

Zhang,Yanmin; Zhang,Yusen; Li,Minghua; Meng,Fanhua; Yu,Zhendong; Chen,Yun; Cui,Guanghui

doi:10.3892/or.2019.7088

Combination of SB431542, CHIR99021 and PD0325901 has a synergic effect on abrogating valproic acid‑induced epithelial‑mesenchymal transition and stemness in HeLa, 5637 and SCC‑15 cells

Authors:
- Yanmin Zhang
- Yusen Zhang
- Minghua Li
- Fanhua Meng
- Zhendong Yu
- Yun Chen
- Guanghui Cui
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Affiliations: Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China, Ultrasound Department, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China, Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China, Reproductive Medicine Center, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
Published online on: April 1, 2019 https://doi.org/10.3892/or.2019.7088
Pages: 3545-3554

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Abstract

Epithelial‑mesenchymal transition (EMT) plays an important role in cancer progression, metastasis and drug resistance, and recent studies have revealed that neoplastic epithelial cells regain the stem cell state through EMT. Single‑agent targeted cancer therapy frequently fails due to acquired drug resistance. Therefore, multi‑agent targeted therapy exhibits advantages in fighting cancer cells. In the present study, small molecule inhibitors SB431542 (ALK inhibitor), CHIR99021 (GSK3 pathway inhibitor), PD0325901 (MEK/ERK inhibitor) and valproic acid (VPA; HDAC inhibitor) were applied individually or in combination to HeLa uterine cervix carcinoma cells, 5637 bladder cancer cells and SCC‑15 squamous cell carcinoma cells to clarify their potential effects on cancer cells. Cell morphological alterations, pluripotency and EMT‑related gene expression, cell growth rate, cell migration, signal transduction, cell cycle arrest, CD24‑/CD44+ cell percentage, and in vivo tumor clump formation were evaluated. The results of the present study revealed that VPA treatment induced EMT morphology, upregulated the expression of pluripotency and EMT‑related genes, promoted migration and increased CD24‑/CD44+ cell percentage in all three cell lines. PD0325901, SB431542 and CHIR99021 in combination could significantly inhibit cell growth, suppress expression of pluripotency and EMT‑related genes, curb cell migration, cause cell cycle arrest, decrease CD24‑/CD44+ cell percentage in cell spheres, and delay in vivo cell clump formation of cancer cells. These data indicated that VPA may serve as an EMT and cancer stem cell‑promoting agent that may be useful in establishing a screening system for potential anticancer stem cell drugs. The combined inhibition of MEK/ERK, ALK and GSK3 was revealed to be an effective measure for eliminating cancer stem cells.

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