Acquisition of anticancer drug resistance is partially associated with cancer stemness in human colon cancer cells

Abstract

Colorectal cancer (CRC) is one of the most aggressive cancers worldwide. Several anticancer agents are available to treat CRC, but eventually cancer relapse occurs. One major cause of chemotherapy failure is the emergence of drug-resistant tumor cells, suspected to originate from the stem cell compartment. The aim of this study was to ask whether drug resistance was associated with the acquisition of stem cell-like properties. We isolated drug-resistant derivatives of two human CRC cell lines, HT29 and HCT116, using two anticancer drugs with distinct modes of action, oxaliplatin and docetaxel. HT29 cells resistant to oxaliplatin and both HT29 and HCT116 cells resistant to docetaxel were characterized for their expression of genes potentially involved in drug resistance, cell growth and cell division, and by surveying stem cell-like phenotypic traits, including marker genes, the ability to repair cell-wound and to form colonospheres. Among the genes involved in platinum or taxane resistance (MDR1, ABCG2, MRP2 or ATP7B), MDR1 was uniquely overexpressed in all the resistant cells. An increase in the cyclin-dependent kinase inhibitor p21, in cyclin D1 and in CD26, CD166 cancer stem cell markers, was noted in the resistant cells, together with a higher ability to form larger and more abundant colonospheres. However, many phenotypic traits were selectively altered in either HT29- or in HCT116-resistant cells. Expression of EPHB2, ITGβ-1 or Myc was specifically increased in the HT29-resistant cells, whereas only HCT116-resistant cells efficiently repaired cell- wounds. Taken together, our results show that human CRC cells selected for their resistance to anticancer drugs displayed a few stem cell characteristics, a small fraction of which was shared between cell lines. The occurrence of marked phenotypic differences between HT29- and HCT116-drug resistant cells indicates that the acquired resistance depends mostly on the parental cell characteristics, rather than on the drug type used.

Cytotoxic effects of the newly-developed chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines

“…Suppression of survivin contributed by increasing drug sensitivity to HSP90 inhibitor agents in HT-29 cells( 36 ). However, HT-29 compared with HCT-116 had higher expression levels of EPHB2, ITGβ-1, and Myc; overexpression of these genes is related to the acquisition of anticancer drug resistance( 37 ). To the best of the authors' knowledge, no study has reported the effects of 17AAG/oxaliplatin/capecitabine triple combinations in any cell lines.…”

Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP

“…In CRC, it is well established the transcriptional activation of certain genes such as c-Myc and Cyclin D, which are two positive cell cycle regulators associated with tumor intestinal cells proliferation (El Khoury et al, 2016). In vitro we previously demonstrated that PTHrP increases the amount of these proteins in tumor intestinal cells (Martín et al, 2014) and herein we showed that the hormone also up-regulates Cyclin D protein expression in vivo; furthermore, this peptide positively modulates cell cycle progression and changes the expression of other proteins involved in cell cycle regulation via MAPK pathway (Calvo et al, 2014).…”

In Vitro Toxicity of Asparagus Saponins in Distinct Multidrug‐Resistant Colon Cancer Cells

“…Since MDR is the major cause for the reduced effects of chemotherapy, MDR cells lines were used for the identification of novel antitumor compounds. [29] In order to find the best strategy for selecting the suitable agents for chemo-resistant tumors, in this research we used three different colon cancer cell lines and first we established the resistance of these cells using increasing concentrations of the anticancer drug, 5-FU. The results showed that Caco-2 cells were less resistant to this anticancer drug, while the other two lines could be used as models for the MDR colon cell lines.…”