Abstract
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment. HepG2 cells were cultured under normoxic and hypoxic conditions exposed to doxorubicin, rapamycin and combinations thereof, and analyzed for viability and the expression of hypoxia-induced HIF-1α in response to these treatments. A pilot study was carried out to evaluate the antitumour effects of these drug combinations delivered from drug-eluting beads in vivo using an ectopic xenograft murine model of HCC. A therapeutic doxorubicin concentration that inhibits the viability of normoxic and hypoxic HepG2 cells and above which hypoxic cells are chemoresistant was identified, together with the lowest effective dose of rapamycin against normoxic and hypoxic HepG2 cells. It was shown that combinations of rapamycin and doxorubicin are more effective than doxorubicin alone. Western Blotting indicated that both doxorubicin and rapamycin inhibit hypoxia-induced accumulation of HIF-1α. Combination treatments were more effective in vivo than either treatment alone. mTOR inhibition can improve outcomes of doxorubicin treatment in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths [1]; it is often diagnosed at an intermediate or an advanced stage, when treatment options are limited and the prognosis is poor
The effects of doxorubicin, rapamycin and combinations on cell viability under normoxic and hypoxic conditions To determine the effect of doxorubicin, rapamycin and combinations of both on HepG2 cell viability, a series of time-dependent and concentration-dependent MTS assays were carried out
After 48 h (Fig. 1a), 10, 25 and 50 μmol/l doxorubicin treatments all reduced the viability of HepG2 cells cultured under normoxic conditions (P = 0.000, 0.002 and 0.004, respectively)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths [1]; it is often diagnosed at an intermediate or an advanced stage, when treatment options are limited and the prognosis is poor. Disruption of the arterial blood supply results in a depletion of oxygen and nutrients to the tumour cells, and consequent necrosis and tumour. Drug-eluting bead transarterial chemoembolization (DEB-TACE) is a refinement of TACE and provides a one-step procedure for both embolization and drug delivery. DEB-TACE enables a controlled, localized and sustained release of the drug to the tumour bed, with reduced systemic doxorubicin and an improved safety profile compared with cTACE [5,6,7]. A feature of the embolization of the blood vessels is the generation of ischaemia, which is the primary cause of tumour cell death following this procedure, but that may have downstream ramifications
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