Lobaplatin promotes radiosensitivity, induces apoptosis, attenuates cancer stemness and inhibits proliferation through PI3K/AKT pathway in esophageal squamous cell carcinoma

Biomed Pharmacother. 2018 Jun:102:567-574. doi: 10.1016/j.biopha.2018.03.109. Epub 2018 Apr 5.

Abstract

Radiotherapy is one of the common treatments for esophageal squamous cell carcinoma (ESCC). Yet, local recurrence led by radioresistance is still not solved. Lobaplatin (LBP) is known to have powerful clinical anti-tumor activities in various tumors, but its effect in radiotherapy is rarely studied. Here we report that LBP is a promising radiosensitizer for ESCC. We treated ESCC cells with LBP and radiation, both separately and in combination. Untreated cells were set as control groups. We found that LBP inhibited ESCC cell growth and enhanced their radiosensitivity. LBP also impeded the tumor growth in vivo. LBP combined with radiation significantly increased ESCC cell apoptosis. Meanwhile, LBP obviously decreased the expression of cancer stem cells biomarker CD271 both in vitro and in vivo. The molecular mechanism was related to the downregulation of Bcl-2/Bax ratio, PI3K and p-AKT (Ser473) expression. Taken together, our findings indicated that LBP could enhance the radiosensitivity of ESCC cells by increasing radiation-induced apoptosis, attenuating cancer stemness and inhibiting PI3K/AKT pathway. These results provide a foundation for the combined therapy of radiation and LBP for ESCC in clinical practice.

Keywords: Apoptosis; Cancer stem cells; Esophageal squamous carcinoma; Lobaplatin; PI3K; Radiosensitivity.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclobutanes / pharmacology
  • Cyclobutanes / therapeutic use*
  • Down-Regulation / drug effects
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / enzymology*
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma
  • Female
  • Humans
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Nerve Tissue Proteins
  • Organoplatinum Compounds / pharmacology
  • Organoplatinum Compounds / therapeutic use*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Radiation Tolerance* / drug effects
  • Receptors, Nerve Growth Factor
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects
  • bcl-2-Associated X Protein / metabolism

Substances

  • Cyclobutanes
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Organoplatinum Compounds
  • Receptors, Nerve Growth Factor
  • bcl-2-Associated X Protein
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • lobaplatin