Establishment and characterization of triple drug resistant head and neck squamous cell carcinoma cell lines

Abstract

Resistance to chemotherapy leading to poor outcome and survival remains a challenge for developing strategies for therapeutic interventions in all types of cancer, including head and neck cancer. In vitro chemoresistant cell line models are an indispensable resource towards delineating the mechanisms involved in drug resistance/response and for the development of novel drugs. Current treatment for head and neck cancer includes chemotherapy with cisplatin, docetaxel and 5-fluorouracil (5-FU) and the response rates to these drugs in patients is 60-80%. The present study aimed to generate head and neck cancer triple drug-resistant cell lines in an effort towards elucidating the mechanisms underlying chemoresistance and providing a resourceful tool for drug design. Using two head and neck squamous cell carcinoma cell lines, Hep-2 (larynx) and CAL-27 (oral cavity), the present study sequentially exposed these cells to increasing concentrations of the combination of docetaxel, cisplatin and 5-FU (TPF) to generate triple drug-resistant cells, termed Hep-2 TPF resistant (TPFR) and CAL-27 TPFR. The effect of the drug treatments on the cell viability, apoptosis, cell cycle and the expression of genes associated with multidrug resistance were analyzed in the parental cells and drug-resistant counterparts.

Molecular Mechanisms of Chemotherapy Resistance in Head and Neck Cancers

“…It is worth noting that multidrug cross-resistance mechanisms possibly occur on HNC cells. As previously reported, triple drugs (docetaxel, cisplatin, and 5−FU) −resistant HNSCC cell lines (Hep−2 and CAL−27) exhibited higher chemotherapy resistance, reduced apoptotic cell death, and an increased expression of MDR1, MRP2, ERCC1, CTR, Survivin, and TS (88), which suggests that multiple drug-resistant HNSCC cells can simultaneously have multidrug cross-resistance mechanisms, including DNA/RNA damage repair, drug efflux, and apoptosis inhibition.…”

Current Omics Trends in Personalised Head and Neck Cancer Chemoradiotherapy

“…A common drug cocktail employed in HNC chemotherapy due to its potential synergistic effect is the combination of cisplatin, docetaxel, and 5-FU. To elucidate some of the mechanisms behind drug resistance triggered by this drug combination, triple-drugresistant cell lines were generated by exposing the cell lines to increasing drug concentrations [44]. The study aimed to evaluate both cellular and molecular effects by assessing cell viability, cell cycle properties, apoptosis, and gene expression associated with multidrug resistance.…”

“…Table 2 is a compilation of gene mutations responsible for chemotherapy resistance. [44] Critical role within the nucleotide excision repair system of DNA Excision repair cross-complementation group 4 XPF (ERCC4) (Vaezi et al, 2011) [46] Protein involved in DNA binding and protein-protein interaction Lumican (LUM) (Yamano et al, 2010) [41] Proteoglycan involved in epithelial cell migration and tissue repair Cyclic nucleotide phosphodiesterase type 3 (PDE3B) (Yamano et al, 2010) [41] Intracellular messengers that regulate numerous signalling pathways Platelet-derived growth factor C (PDGF-C) (Yamano et al, 2010) [41] Important role in connective tissue growth and function. Belongs to the PDGF/vascular endothelial growth factor family Next to drug resistance, chemotoxicity is another factor limiting the success of chemotherapy.…”

H19/miR‐107/HMGB1 axis sensitizes laryngeal squamous cell carcinoma to cisplatin by suppressing autophagy in vitro and in vivo

“…Studies have shown that 95% of the LSCC has poor sensitivity to chemotherapy. Thus, treatment of LSCC is largely ineffective due to the resistance of the tumor cells to chemotherapy (Govindan et al, 2015). However, the resistance mechanism of LSCC cells is still unclear and the corresponding effective way to suppress drug resistance is also elusive.…”