Research ArticleExperimental Studies

Comparative Chemosensitivity of VX2 and HCC Cell Lines to Drugs Used in TACE

FLORENTINA PASCALE, LAURENT BEDOUET, MINTHAM BAYLATRY, JULIEN NAMUR and ALEXANDRE LAURENT
Anticancer Research December 2015, 35 (12) 6497-6503;

Abstract

Aim: To compare the cytotoxic effects of 11 anticancer agents against VX2 and HepG2 cells in order to establish candidate drugs that can be tested preclinically on VX2 tumor model for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). Materials and Methods: VX2 and HepG2 cells were incubated with different drug concentrations. The half-maximal inhibitory concentration (IC50) values were determined by total cell protein assay for anthracyclines, platins, irinotecan, mytomicin-C (MMC), 5-fluorouracil (5-FU) and antiangiogenics. Results: IC50 values for VX2 and HepG2 were found close for doxorubicin (0.8 μM vs. 1.1 μM), MMC (13.9 μM vs. 8.7 μM), sunitinib (32.7 vs. 33.7 μM), sorafenib (10.3 vs. 8.9 μM), lapatinib (30 vs. 18.3 μM) and different for platins and irinotecan. Oxaliplatin was less active against VX2 than HepG2 (IC50=41 μM vs. 2.7 μM), cisplatin was more active against VX2 than HepG2 (IC50=8.0 μM vs. 15.9 μM), whereas carboplatin had a low toxicity against both cell lines (70.4 μM vs. 538.3 μM). The toxicity of 5-FU against VX2 and HepG2 was low (IC50=560.6 μM vs. 323.2 μM). Irinotecan was less active against VX2 vs. HepG2 (IC50=44.5 μM vs. 15.3 μM). Bevacizumab had no effect on either of the cell lines up to 6.7 μM. Conclusion: Drugs recommended for pre-clinical trials of TACE in the VX2 model are doxorubicin, sunitinib, sorafenib, MMC, lapatinib and 5-FU.

Hepatocellular carcinoma (HCC) is highly resistant to pharmacological treatment (1-3). Conventional i.v. chemotherapy with anti-neoplastic drugs is not part of the Barcelona Clinic Liver Cancer treatment strategy (4). However these drugs can now be loaded inside calibrated microspheres and be delivered directly to the tumor by a transarterial catheter approach. The local concentration of the anticancer agent is thus increased compared to that of systemic therapy and can be maintained at high levels for several hours to several days (5-9).

It appears essential to collect data on the native sensitivity of cancer cells to the chemotherapeutic drugs before starting a local therapy such as transarterial chemoembolization (TACE). Moreover, in studies with TACE, it is necessary to know the effect of the chemotherapeutic drugs irrespective of the ischemic effect of the particles per se on the tissues (7).

The VX2 liver tumor model is extensively used in pre-clinical trials of TACE for HCC with various drugs and drug-eluting microspheres (6, 8, 10, 11). The VX2 tumor is very similar to human HCC in terms of vascularization (11) and well-characterized in terms of growth, histology and molecular biology (12-14). However, the sensitivity of the VX2 cells to the drugs commonly used in TACE is not known and may differ from that of human hepatocarcinoma since they originate from different species (human and rabbit) and different tumors (hepatocarcinoma and squamous epithelioma).

The aim of the present in vitro screening study was to provide a comparative overview on the native chemo-resistance of VX2 and HCC cell lines to the cytotoxic effects of 11 anticancer agents in order to establish candidate drugs that can be accurately tested in TACE in the VX2 tumor model.

Materials and Methods

Cell culture. The HepG2 cell line [HepG2/C3A, derivative of HepG2 (ATCC® CRL10741; American Type Culture Collection, Manassas, VA, USA), was cultured (37°C, 5% CO2) in MEM GlutaMAX with 10% SVF and antibiotics (100 UI penicillin, 10 μg/ml streptomycin; GIBCO-Invitrogen, Invitrogen Life Technologies SAS, Saint Aubin, France).

The VX2 cell line was cultured according to Pascale et al. (13). Cells were seeded in 96-well tissue culture plates (1.5×104 cells for VX2 and 4.5×104 cells for HepG2) in 100 μl of culture medium. After 24 h (80% confluence), drugs were added to eight wells at a wide range of concentrations (1-3).

Drugs. Drugs commonly used in TACE of HCC (7) were compared: i.e. anthracyclines (doxorubicin), platins (oxaliplatin, carboplatin and cisplatin) and mytomicin C (MMC). Additionally, drugs that have been proposed as candidates for loading and local release through drug-eluting embolics have been investigated: drugs used for liver metastases irinotecan, 5-fluorouracil (5-FU) and four antiangiogenic drugs (sunitinib, sorafenib, lapatinib and bevacizumab).

Commercially available solutions were used for seven anticancer agents: doxorubicin (Adriblastin®, 2.5 mg/ml; Pfizer, Paris, France), oxaliplatin (Oxaliplatin, 5 mg/ml; Accord Healthcare Laboratory, Lille, France), carboplatin (Carboplatin, 10 mg/ml; Teva Laboratory, Courbevoie, France), cisplatin (Cisplatin,1 mg/ml; Mylan Laboratory, Saint Priest, France), irinotecan (Camptosar, 20 mg/ml Pfizer, Paris, France), 5-FU (Fluorouracile Ebewe, 50 mg/ml; Sandoz Laboratory, Levallois-Perret, France) and bevacizumab (Avastin, 25 mg/ml; F. Hoffmann-La Roche AG, Basel Switzerland). For four drugs, we used powder to prepare stock solutions as follows: MMC (50 mg containing 2 mg MMC, 0.5 mg/ml; Sigma-Aldrich Chemie, Saint-Quentin Fallavier, France), sunitinib (Sunitinib malate salt, LC Laboratories, Woburn, MA, USA), sorafenib (BioVision Inc., Milpitas CA, USA) and lapatinib (Alfa Aesar Laboratory, Ward Hill, MA,USA), were solubilized in dimethyl sulfoxide (DMSO).

Untreated cells were cultured under the same conditions as treated cells without drug exposure and were considered as controls, with 100% survival. For drugs solubilized in DMSO, control cells were cultured with the same amount of vehicle as treated cells to exclude the potential toxic effect of DMSO.

Cell viability analysis by total cell protein assay. After 72 h, cytotoxicity was analyzed according to a colorimetric protein assay with bicinchoninic acid (BCA) (Sigma-Aldrich, St. Louis, MO, USA) (15).

Cells were washed with phosphate-buffered saline (PBS) and proteins from adherent surviving cells were solubilized by 100 μl of BCA containing 0.05% Triton X-100 per well. After 30 min (37°C), the optical density was read at 560 nm (MultiskanTM GO Microplate spectrophotometer; Thermo Fischer Scientific, Villebon sur Yvette, France). The protein content was determined according to a standard curve obtained with bovine serum albumin (BSA; Sigma Aldrich).

The results were expressed as total protein content as an indicator of cell viability, then as a percentage from that of the control cells by use of the formula: viability (protein content, % of control)=A/B×100, where A is the protein concentration of the treated monolayer, and B is the protein concentration of the control.

View this table:
Table I.

Half-maximal inhibitory concentration (IC50) for 10 chemotherapeutic drugs tested on VX2 and HepG2 cells. Fold change is the ratio between the IC50 for VX2 and IC50 HepG2. A minimum twofold change was the criterion used to select drugs with different activity for both cell lines. Negative fold change values correspond to the drugs more active against VX2 cells and positive values correspond to the drugs less active against VX2.

Each point of the concentration–protein content curves represents the mean of the ratio of the protein content of treated cells to that of the corresponding control cells, obtained from eight measurements. The IC50 represented the drug concentration that reduced the protein content of the cell monolayer by 50%. It was calculated from the concentration–response curves by linear interpolation (16).

Each point of the concentration–protein content curves was compared between the two cell lines by a non-parametric Mann-Whitney U-test (MW) (Statview version 5.0; SAS Institute, Inc, Cary, NC, USA). The differences were considered significant when p<0.05.

The chemosensitivity to each drug was compared by calculating the fold change (ratio) between the IC50 for VX2 and HepG2 cells.

Results

The IC50 values were determined for all drugs tested during this study (Table I) except for bevacizumab, which had no effect on the proliferation of VX2 and HepG2 cells.

The sensitivities to doxorubicin were very close for VX2 and HepG2 cells (IC50=0.8 vs. 1.1 μM, respectively) (Figure 1a and Table I), even if the difference between some points of the curves was statistically different. The fold change of IC was −1.33, meaning that the concentration of doxorubicin required to achieve a 50% decrease of cell viability was 1.33-times lower for VX2 than HepG2 cells.

The sensitivity to MMC was slightly but significantly lower for VX2 than HepG2 cells (IC50=13.9 μM vs. 8.7 μM) (Figure 1b). The fold change of IC50 was +1.60, meaning that the concentration of MMC required to achieve a 50% decrease of cell viability was 1.60-times higher for VX2 than HepG2.

Figure 1.
Figure 1.

Viability curves representing the comparative cytotoxicity of doxorubicin (a), mytomicin C (MMC; b), 5-fluorouracil (5-FU; c) and irinotecan (d) against VX2 and HepG2 cells after 72 h of culture. Cytotoxicity was measured by a quantitative colorimetric protein assay. *p<0.05, **p<0.01, ***p<0.001.

The IC50 for 5-FU was elevated for both cell lines and was significantly higher for VX2 compared to HepG2 (560.6 μM and 323.2 μM respectively, fold change 1.73) (Figure 1c).

VX2 cells were less sensitive than HepG2 to irinotecan (IC50=44.5 μM vs. 15.3 μM, fold change 2.9) (Figure 1d, Table I).

VX2 cells were also less sensitive to oxaliplatin (IC50=41 μM vs. 2.7 μM, fold change 15.47) (Figure 2a) but more sensitive to cisplatin than HepG2 (IC50=8.0 vs. 15.9 μM, fold change 2) (Figure 2c). Carboplatin was more toxic for VX2 cells than for HepG2 but the IC50 reached quite high values for both cell lines (70.4 μM and 538 μM, fold change 7.69) (Figure 2b).

IC50 did not significantly differ between VX2 and HepG2 cells for the two tyrosine kinase inhibitors sunitinib (32.7 vs. 33.7 μM, fold change 1.03) and sorafenib (10.3 vs. 8.9 μM, fold change 1.15) (Figure 3a and b, Table I). VX2 cells were more sensitive to lapatinib than HepG2 (IC50=18.3 μM vs. 30 μM, fold change 1.64) (Figure 3c). No cytotoxic effect was observed for either cell line on treatment with bevacizumab even at the highest concentration (Figure 3d).

Figure 2.
Figure 2.

Viability curves representing the comparative cytotoxicity of the platins oxaliplatin (a), carboplatin (b), and cisplatin (c) against VX2 and HepG2 after 72 h of culture. Cytotoxicity was measured by a quantitative colorimetric protein assay. *p<0.05, **p<0.01, ***p<0.001.

Discussion

The present in vitro findings on HepG2 and VX2 tumor cell lines provide an overview of the respective cytotoxic effects of anticancer drugs commonly used in TACE of HCC.

The chemosensitivities measured here for HepG2 cells were in good agreement with existing data in the literature. As expected, doxorubicin was found to be one of the most toxic drugs among the chemotherapeutic agents (2, 3). MMC, irinotecan and 5-FU had less effect on the viability of the cells, with IC50 in the same range as previously reported for this cell line (2, 3). Among platin derivatives, oxaliplatin was the most effective at reducing cell viability, followed by cisplatin (3). The antiproliferative effect of carboplatin was markedly lower than for both these platins (1-3), with an IC50 value lower than previously reported (2), probably due to a longer drug exposure time under our experimental conditions (72 h vs. 0.5 h).

For sorafenib, the IC50 measured in the present study was in good agreement with the values previously reported against HepG2 (17) and other hepatocarcinoma cell lines (18). The IC50 values for lapatinib and sunitinib were much higher than previously found (19, 20), and this discrepancy might be explained by a difference in the methods of viability assessment or a difference in the density of the cell monolayer which may affect the chemosensitivity (21).

Figure 3.
Figure 3.

Viability curves representing the comparative cytotoxicity of antiangiogenics sunitinib (a), sorafenib (b), lapatinib (c) and bevacizumab (d) against VX2 and HepG2 cells after 72 h of culture. Cytotoxicity was measured by a quantitative colorimetric protein assay. *p<0.05, **p<0.01, ***p<0.001.

Interestingly, the three antiangiogenic drugs significantly reduced the viability of tumor cells in the same range of concentration as the cytotoxic agents. The antiangiogenic drugs may also have a direct antiproliferative effect on tumor cells. It is known that sunitinib primarily acts as an antiangiogenic agent at nanomolar concentrations (22) and as an antiproliferative drug at micromolar concentrations (23). Therefore, it can be reasonably expected that the local delivery of micromolar doses of antiangiogenics by drug-eluting particles can induce tumor necrosis similarly to other antineoplastic drugs.

Bevacizumab had no cytotoxic effect on cellular viability for both cell lines, as already reported for HepG2 and other hepatocarcinoma cell lines treated with concentrations up to 100 mg/ml (24). One explanation could be that bevacizumab binds to vascular endothelial growth factor (VEGF), preventing the interaction of VEGF with its receptors that are mostly distributed on endothelial cells, but has no direct effect on the tumor cells themselves.

When comparing the chemosensitivities of HepG2 and VX2 tumor cell lines, a similar or close activity (fold change of less than 2) was noted for doxorubicin, the three antiangiogenic drugs sunitinib, sorafenib and lapatinib, and MMC and 5-FU. These drugs may share similar signaling pathways and pharmacodynamics in the two cell lines. In addition, this finding further supports the relevance of VX2-bearing rabbits for evaluating these drugs or drug-eluting particles loaded with these agents.

TACE with doxorubicin-eluting beads (DEB-DOX) in rabbit VX2 tumor resulted in immediate concentrations of high levels of doxorubicin in tumors: 413 μM at 3 days, remaining high at 7 days (116.7 μM) and even at 14 days (41.76 μM) after treatment (6). Whatever the delay, DEB-DOX enables the sustained release of doxorubicin to hepatic tumors at levels that are broadly above the IC50 of 0.8 μM that we found in vitro. These concentrations are correlated with 90-100% of tumoral necrosis (6). In human HCC, the tissue concentration of doxorubicin reached 5 μM 8 h after TACE with DEB-DOX and 2.1 μM 15 days later; one month after embolization, the doxorubicin concentration dropped to 0.65 μM, below the IC50 value of 1.1 μM found in vitro for HepG2 (9). This means that doxorubicin-eluting microspheres could provide a high level of drug immediately after TACE and gradually, for a period of 2 weeks, elute a quantity of drug that is superior to the threshold of cytotoxicity found in vitro.

Few data are available from pre-clinical trials with TACE and antiangiogenics. Sunitinib-eluting microspheres in healthy rabbit liver resulted in immediate increase in high concentrations of sunitinib, reaching 25 μM at 6 h and decreasing to 5.97 μM 24 h after TACE (25). Two weeks after embolization of VX2 tumors with sunitinib-loaded beads of different sizes, the concentration of sunitinib in tumors was measured at 31 μM, a level similar to the IC50 found in our study for both cell lines (32.7 μM) (5). These consistent findings indicate that sunitinib-eluting beads (30 mg/ml) are able to provide a sustained release of a sufficient amount of drug with a great efficiency against tumor angiogenesis and tumor development, and induce extensive tumor necrosis (5).

The difference in the IC50 was greater than two-fold between HepG2 and VX2 tumor cell lines for irinotecan, oxaliplatin, carboplatin and cisplatin. VX2 cells were less sensitive to irinotecan than HepG2. Irrespective of time points, the level of irinotecan achieved by drug-eluting embolics in VX2 tumors is much lower than the IC50 found here (8, 26). Irinotecan is a prodrug that is converted to an active metabolite, SN-38, by plasma or tissue carboxyl-esterase. SN-38 is 1,000-times more active than the prodrug (26). As the rabbit carboxyl-esterase is 100 to 1,000 times more efficient than the human enzyme for converting irinotecan into SN-38 (27), it remains intriguing that irinotecan is not more active against VX2 cells. We hypothesize that the carboxyl-esterase is less expressed or less active in the VX2 cell line, or that the mechanisms of drug resistance described for some hepatocarcinoma cell lines (26) are enhanced for VX2 cells. Future studies should test the cytotoxicity of SN-38 on both cell lines to elucidate if the lower efficiency of irinotecan against VX2 cells in vitro is the result of a poor conversion of the prodrug into SN-38 or of the weak action of SN-38 on VX2 cells.

Variable differences were noted between the three platins in both cell lines. Oxaliplatin was much more active against HepG2 cells than VX2 cells, whereas carboplatin and cisplatin were much more active against VX2 cells. These findings suggest that the outcomes from the VX2 trials of TACE with oxaliplatin, cisplatin and carboplatin should be cautiously interpreted, as HCC may have a different sensitivity to these drugs.

Limitations and perspectives. Our system for testing drug chemosensitivity in two dimensions allowed for comparison between two standardized cell lines, one of them commonly used as experimental cells for HCC models (HepG2) and the second for pre-clinical evaluation of drug-eluting microspheres (VX2). It is hypothesized that properties measured in vitro may be translated into properties in vivo. It would be interesting to compare the IC50 determined in the present study and the tissue concentrations of drug obtained in vivo after chemoembolization to determine firstly, if the drug delivered by the TACE procedure can be maintained at levels corresponding to the threshold of cytotoxicity for a long period of time, and secondly, to compare the IC50 in vitro and the concentration of drug necessary to obtain an anti-tumoral action in vivo (growth, necrosis). In addition, histocultures from VX2 tumors could be performed to evaluate the activity of anticancer drugs in order to more closely approximate the 3D in vivo situation.

Conclusion

The present in vitro findings on HepG2 and VX2 tumor cell lines recommended that drugs to be tested in the VX2 tumor model are, in decreasing order: doxorubicin, sunitinib, sorafenib, MMC, lapatinib and 5-FU. Carboplatin, cisplatin and oxaliplatin, which are endowed with very different profiles for the VX2 and HepG2 cell lines, should not be recommended.

Future studies for the development of new drug delivery systems in TACE may adapt the loading and eluting capacity to the threshold of efficacy that can be first estimated in vitro.

  • Received September 21, 2015.
  • Revision received October 23, 2015.
  • Accepted October 29, 2015.

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Comparative Chemosensitivity of VX2 and HCC Cell Lines to Drugs Used in TACE
FLORENTINA PASCALE, LAURENT BEDOUET, MINTHAM BAYLATRY, JULIEN NAMUR, ALEXANDRE LAURENT
Anticancer Research Dec 2015, 35 (12) 6497-6503;
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