Targeting lung cancer stem cells using combination of Tel and Docetaxel liposomes in 3D cultures and tumor xenografts

Toxicol Appl Pharmacol. 2020 Aug 15;401:115112. doi: 10.1016/j.taap.2020.115112. Epub 2020 Jun 12.

Abstract

Cancer stem cells (CSCs) accounts for recurrence and resistance to chemotherapy in various tumors. Efficacy of chemotherapeutic drugs is limited by tumor stromal barriers, which hinder their penetration into deep tumor sites. We have earlier shown telmisartan (Tel) pretreatment prior to Docetaxel (DTX) administration enhances anti-cancer effects in non-small cell lung cancer (NSCLC). Herein, we demonstrated for the first time the efficacy of Docetaxel liposomes (DTXPL) in combination with Tel in 3D cultures of H460 cells by using polysaccharide-based hydrogels (TheWell Biosciences) and also in xenograft model of DTX resistant H460 derived CD133+ lung tumors. DTXPL and Tel combination showed enhanced cytotoxicity in H460 WT 3D cultures by two folds. In H460 3D cultures, Tel pretreatment showed increased liposomal uptake. DTXPL and Tel combination treated tumors showed reduction in tumor volume (p < .001), increased apoptosis and downregulation of CSC markers (p < .01) in H460 WT and DTX resistant CD133+ xenograft models.

Keywords: Cancer Stem Cells (CSC); Docetaxel (DTX); Docetaxel Loaded PEGylated Liposomes (DTXPL); Non-small Cell Lung Cancer (NSCLC); Resistance; Telmisartan (Tel).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Docetaxel / administration & dosage*
  • Drug Delivery Systems / methods*
  • Female
  • Humans
  • Liposomes
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Telmisartan / administration & dosage*
  • Xenograft Model Antitumor Assays / methods*

Substances

  • Antineoplastic Agents
  • Liposomes
  • Docetaxel
  • Telmisartan