Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment in�vitro

Abstract

Abstract. Transarterial chemoembolization (TACE) is an established therapeutic approach for the treatment of hepatocellular carcinoma (HCC). Although patients who undergo TACE may have prolonged survival, there are indications that the malignancy of residual HCC tissue can increase subsequent to the procedure. Although hypoxia, which occurs during TACE due to ischemia, is known to contribute to angiogenesis, little is known with regard to the undesirable effects of chemotherapeutic agents on residual HCC cells. Doxorubicin is one of the most commonly used drugs in TACE. The aim of the present study was to analyze alterations in Hep3B and HepG2 human HCC cell lines surviving doxorubicin treatment in vitro. Initially, the toxic concentration range was determined, and doxorubicin was subsequently applied in concentrations that killed >80% of the HCC cells. During the first days subsequent to treatment, surviving cells had higher expression levels of the epithelial-mesenchymal transition marker SNAIL, and exhibited increased migratory activity compared with control cells. At 3 weeks after the first doxorubicin treatment, surviving HCC cells tolerated significantly higher doxorubicin concentrations compared with control cells. As a potential explanation for this doxorubicin resistance, significantly increased mRNA expression levels of ATP-binding cassette ABCB1 (multidrug resistance protein 1) and ABCC1 (multidrug resistance-associated protein 1) were observed by reverse transcription-quantitative polymerase chain reaction. In summary, these findings indicate that, following TACE treatment, hypoxia as well as doxorubicin may induce a more malignant phenotype in surviving HCC cells and decrease susceptibility to further chemotherapeutic treatment.

LncRNA CRNDE facilitates epigenetic suppression of CELF2 and LATS2 to promote proliferation, migration and chemoresistance in hepatocellular carcinoma

“…Drug resistance arises commonly in cancers and leads to the failure of chemotherapy in nearly all advanced patients 54 , 55 . HCC is one of the most malignant cancer types yet displayed rather low chemosensitivity 56 , 57 . In order to finally overcome the chemoresistance and maximize the chemotherapy benefits in HCC, many efforts should be made toward a better understanding of the underlying mechanism 58 .…”

Pretreatment Heterogeneous Enhancement Pattern of Hepatocellular Carcinoma May Be a Useful New Predictor of Early Response to Lenvatinib and Overall Prognosis

“…In addition, 41 of 51 patients (80%) presented TACE failure/refractoriness, and the high number of TACE treatments (median of 3) before initiation of lenvatinib may have caused the high distribution of heterogeneously enhanced target nodules in this cohort. Previously, other researchers reported that TACE treatment induced a more malignant phenotype of HCC, including poorly-differentiated histology and CK19 expression indicative of the more aggressive biliary phenotype [33, 34].…”

Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile

“…Several mechanisms have been described to contribute to the acquired resistance to DOX [39]. Firstly, an upregulation of multidrug resistance efflux pumps could create a reduction in nuclear drug accumulation [40]. Unfortunately, the biomarkers analyzed with the oncology panel did not represent proteins for drug response, which could be why there were no noticeable differences in hierarchical clustering on treatment levels.…”