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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2003.03.010 on November 10, 2003

Annals of Surgical Oncology 10:1184-1190 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Interferon-ß Is More Potent Than Interferon-{alpha} in Inhibition of Human Hepatocellular Carcinoma Cell Growth When Used Alone and in Combination With Anticancer Drugs

Bazarragchaa Damdinsuren, MD, Hiroaki Nagano, PhD, Masato Sakon, PhD, Motoi Kondo, PhD, Tameyoshi Yamamoto, MD, Koji Umeshita, PhD, Keizo Dono, PhD, Shoji Nakamori, PhD and Morito Monden, PhD

From the Department of Surgery and Clinical Oncology (E2), Graduate School of Medicine, Osaka University, Osaka, Japan.

Correspondence: Address correspondence and reprint requests to: Masato Sakon, PhD, Department of Surgery and Clinical Oncology (E2), Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565–0871, Japan; Fax: 81-6-6879-3259; E-mail: msakon{at}surg2.med osaka-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor, but promising effects of chemotherapies combined with interferon (IFN) have been reported.

Methods: To develop more effective combination therapies for HCC, we compared the antiproliferative effects of IFN-{alpha} and IFN-ß in combination with various cytotoxic drugs on hepatoma cell lines using MTT assay and isobologram analysis.

Results: IFN-ß was more potent than IFN-{alpha} in inhibiting the cell growth of all cell lines (P < .05, two-way ANOVA). PLC/PRF/5 was more sensitive to either IFN, than HLE and HuH7. Cell growth of all cell lines was inhibited in a dose-dependent manner by 5-fluorouracil (5-FU), cisplatin (CDDP), and doxorubicin (DOX), but the sensitivities of these cells were considerably different. As for IFN-{alpha}, synergistic effects were observed when combined with 5-FU and DOX on PLC/PRF/5 cells only, whereas IFN-ß showed synergistic effects with 5-FU and CDDP on HuH7 and PLC/PRF/5 cell lines.

Conclusion: The spectra of the antiproliferative activity and synergistic effect of IFN-ß when combined with anticancer drugs are more potent than those of IFN-{alpha}. Combinations of IFN-ß and anticancer drugs may provide a better treatment of HCC when combinations with IFN-{alpha} are ineffective.

Key Words: Interferon • Anticancer drug • Cell proliferation • HCC • Combination therapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and half a million new cases are diagnosed every year.1–3 Despite recent advances in diagnostic modalities for HCC, more than 80% of the new cases are diagnosed in the inoperable, advanced stages of the disease. Unfortunately, the prognosis of such patients is extremely poor, with a 5-year survival of <10%,4,5 and no standard treatment is available for such cases.

Although various chemotherapies have been used for the treatment of HCC, chemotherapeutic agents are generally not effective either when used alone or in combination therapy with other drugs.5 However, recent clinical trials suggested that combination therapy with chemotherapeutic agents and interferon (IFN)-{alpha} may be effective against advanced HCCs,6 including those showing tumor invasion into the major branches of the portal vein.7,8 However, other investigators have reported the ineffectiveness of some of such regimens,9 thus necessitating the need for more effective combination therapies with IFN.

IFNs consist of type I IFN, which includes IFN-{alpha}, -ß, -{omega}, and type II IFN, also known as IFN-{gamma}.10 Although the antiproliferative effects of IFN-{alpha} and -{gamma} have been studied in detail in various cell types, those of IFN-ß are not well understood, especially when it is combined with anticancer drugs. It is also not clear how IFNs modulate the antitumor activity of anticancer drugs in HCC cells.

The present study was designed to compare the antiproliferative effects of IFN-{alpha} and -ß, and of their combinations with chemotherapeutic agents [5-fluorouracil (5-FU), cisplatin (CDDP), and doxorubicin (DOX)] on three hepatoma cell lines, in order to develop a more effective combination therapy for HCC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cell Lines
Three human HCC cell lines, including HLE, HuH7, and PLC/PRF/5, were purchased from the Japanese Cancer Research Resources Bank (Tokyo, Japan). They were maintained in Dulbecco’s Modified Eagle Medium supplemented with 10% fetal bovine serum, 100 units/mL penicillin, and 100 µg/mL streptomycin at 37°C in humidified incubator with 5% CO2 in air.

Drugs and Reagents
Purified human lymphoblast IFN-{alpha} (OIF) was kindly supplied by Otsuka Pharmaceutical Co. (Tokushima, Japan), and its activity was approximately 2.12 x 108 IU/mg. Human natural fibroblast IFN-ß (IFNß Mochida) was provided by Mochida Pharmaceutical Co. (Tokyo, Japan), with a specific activity of 3.7 x 108 IU/mg. 5-FU (Fluorouracil) and DOX (Adriacin) were obtained from Kyowa Hakko Co. (Tokyo), and CDDP (Randa) was purchased from Nippon Kayaku Co. (Tokyo). All drugs were stored at -20°C, and the stock solutions were constituted in distilled water. The concentration of the final compound in the culture medium never exceeded 0.1% in treated samples. MTT (3-[4,5-dimethylthiazol-2yl]-2,5-dipheniltetrazolium bromide) was obtained from Sigma Co. (St. Louis, MO).

Growth Inhibition Assays
Cells (3 x 103/well) were added in triplicate to a 96-well microplate. The medium was replaced 24 hours later by 0.1 mL of fresh medium containing various concentrations of IFN-{alpha} or -ß, with or without different concentrations of 5-FU, CDDP, or DOX. In combination experiments, the test concentrations of IFN-{alpha} were 50 and 500 IU/mL, IFN-ß were 50, 500, and 5000 IU/mL, and those of 5-FU were .05, .5, and 5 µg/mL, CDDP .1, .5, and 1 µg/mL, and DOX .01, .1, and 1 µg/mL. The concentrations of IFNs in growth-inhibitory assays for IFN alone were 50, 500, 5.000, and 25.000 IU/mL. Tumor cells suspended in complete medium were used as a control for cell viability. The medium was changed every 48 hours, and 4 days after the addition of drugs, the number of viable cells was assessed by MTT (Sigma) assay. Briefly, 10 µL (50 µg) of MTT were added to each well, and the plate was incubated for 4 hours at 37°C. Unreacted MTT was then removed, leaving the resultant formazan crystals at the bottom of the well. Then, 0.1 mL of 2-propanol was added to each well to dissolve the crystal. The absorbance of the plate was measured in a microplate reader at a wavelength of 570 nm, and the results were expressed as the percentage of absorbance relative to untreated controls. These assays were repeated at least 3 times, and similar results were obtained.

Evaluation of Cooperative Effects
Synergy of cooperative cytotoxicity was determined by isobole analysis as described by Berenbaum.11 The effect of a particular dose combination for two agents A and B was determined by applying the equation: Ac/Ae + Bc/Be = D, where Ac and Bc correspond to the concentrations of the drugs used in the combination treatment, Ae and Be correspond to the concentrations of the drugs that could produce alone the same magnitude of effect. When D (combination index) < .8, the effect of the combination was synergistic, whereas when (.8 <= D < 1.2) or D >= 1.2, the effect was additive or antagonistic, respectively. Drug potentiation was calculated as the amount of the drug used alone to yield the same effect as the drug in combination divided by the amount of the drug used in the combination.

Statistical Analyses
Statistical analyses were performed using the StatView J-5.0 program (Abacus Concepts Inc., Berkeley, CA). Data are expressed as average of at least three independent experiments, unless stated otherwise. The Mann-Whitney test was used to examine the differences between drug combination groups. The significance of differences of IFNs growth-inhibitory effect or the sensitivities of the cell lines to IFN was calculated by two-way ANOVA. In all analyses, values of P < .05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Antiproliferative Effects of IFN-{alpha} and IFN-ß
The effects of IFN-{alpha} and -ß on cell growth were compared in three human HCC cell lines (HLE, HuH7, and PLC/PRF/5) (Fig. 1). The growth-inhibitory effect of IFN-ß was significantly more potent than that of IFN-{alpha} in all cell lines (P < .05, by two-factor ANOVA). The 50% growth-inhibition concentrations (EC50) of IFN-ß and IFN-{alpha} on PLC/PRF/5 cells were 1.08 x 10-3 and 31.13 x 10-3 µg/mL, respectively, where the antiproliferative effect of the former was 29-fold stronger than the latter.



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  		FIG. 1. Growth-inhibitory effects of IFN-{alpha} and -ß on HCC cell lines. (A) HuH7, (B) PLC/PRF/5, and (C) HLE cells were incubated for 4 days and cell viability was determined as described in Materials and Methods. Proportion of viable cells incubated without IFNs was considered 100%. Data are mean ± SEM of 4 independent experiments. *P < .05, statistical comparison was performed by two-way ANOVA.

 
The sensitivity of cultured cells to the two IFNs was considerably different. No or weak growth-inhibitory effect was observed in HuH7 and HLE cell lines by IFN-{alpha} up to high concentration (where growth inhibition by 20% compared to controls for HuH7 cells were 117.9 x 10-3 and 2.7 x 10-3 µg/ml, or for HLE 18.9 x 10-3 µg/ml and 1.2 x 10-3 µg/mL, for IFN-{alpha} and IFN-ß, respectively), whereas PLC/PRF/5 cells were highly sensitive to both IFNs (where the above growth inhibition effect was reached by 2.7 x 10-3 µg/mL of IFN-{alpha} or by .3 x 10-3 µg/mL of IFN-ß).

Antiproliferative Effects of Combination Treatment of IFNs and Anticancer Drugs
Growth-inhibitory assays were performed to investigate whether IFNs enhance the antiproliferative effects of anticancer drugs on HCC cell lines. The concentrations of chemotherapeutic drugs were selected based on the EC50 of the drugs (data not shown) and the results of previous studies.12

5-FU exhibited a dose-dependent growth-inhibitory effect on all cell lines (Fig. 2) except HLE cells (left panels). When 5-FU and IFN-{alpha} were administered simultaneously, the antiproliferative effects were higher than those of each drug alone in PLC/PRF/5 cells (Fig. 2A). IFN-ß also enhanced the growth-inhibitory effects of 5-FU in a dose-dependent manner in all cell lines (Fig. 2B).



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  		FIG. 2. Growth-inhibitory effects of IFN-{alpha} and -ß in combination of various doses of 5-fluorouracil (5-FU). Cells were incubated with IFN-{alpha} (A) or IFN-ß (B) in the presence of various concentrations of 5-FU and cell proliferation was determined on day 4, as described in Materials and Methods. Proportion of viable cells incubated without drugs was considered 100%. Data are the average of 3 independent experiments. *P < .05, denote significant synergistic effect, as examined by isobologram analysis.

 
CDDP also showed dose-dependent antitumor effects in all cell lines (Fig. 3). The growth inhibition by CDDP was highest in HLE and lowest in PLC/PRF/5 cells. Concurrent application of IFN-{alpha} did not increase the antiproliferative effects of CDDP (Fig. 3A), whereas IFN-ß clearly improved the dose-dependent inhibitory effects of CDDP (Fig. 3B).



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  		FIG. 3. Growth-inhibitory effects of IFN-{alpha} and -ß in combination of various doses of cisplatin (CDDP). Cells were incubated with IFN-{alpha} (A) or IFN-ß (B) in the presence of various concentrations of CDDP and cell proliferation was determined on day 4, as described in Materials and Methods. Proportion of viable cells incubated without drugs was considered 100%. Data are the average of 3 independent experiments. *P < .05, denote significant synergistic effect, as examined by isobologram analysis.

 
The antiproliferative effects of DOX were diverse in the cell lines, showing higher cytotoxicity in HuH7 and HLE and weaker in PLC/PRF/5 cells (Fig. 4). Coincubation of IFN-{alpha} or IFN-ß with DOX enhanced the antiproliferative effects on PLC/PRF/5 cells, but not HLE and HuH7 cells.



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  		FIG. 4. Growth-inhibitory effects of IFN-{alpha} and -ß in combination of various doses of doxorubicin. Cells were incubated with IFN-{alpha} (A) or IFN-ß (B) in the presence of various concentrations of doxorubicin and cell proliferation was determined on day 4, as described in Materials and Methods. Proportion of viable cells incubated without drugs was considered 100%. Data are the average of 3 independent experiments. *P < .05, denote significant synergistic effect, as examined by isobologram analysis.

 
Cooperative Effects of IFNs and Anticancer Drugs
The isobologram analysis was performed for each combination of IFNs and anticancer drugs as described in Materials and Methods, and the results are summarized in Table 1. The cooperative growth-inhibitory patterns were different between combinations of IFN-{alpha} and those of IFN-ß. The latter exhibited more synergistic cooperative effects in HuH7 and PLC/PRF/5. The synergistic effect was observed in PLC/PRF/5 cells in combinations of IFN-{alpha} (50–500 IU/mL) plus 5-FU (.5 µg/mL), and IFN-{alpha} (50 IU/mL) plus DOX (.1 µg/mL). On the other hand, IFN-ß (50 and /or 500 IU/mL) showed a synergistic effect with 5-FU (.5 µg/mL) and CDDP (.5 or .1 µg/mL concentrations) in HuH7 and PLC/PRF/5 cells. In fact, the combinations with IFN-{alpha} or IFN-ß exhibited additive or antagonistic cooperative effects on HLE cell line.


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  		TABLE 1. Cooperative effects of IFN-{alpha} and IFN-ß in combination with anticancer drugs on three hepatoma cell lines
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The clinical efficacy of combination chemotherapy with IFN-{alpha} has already been reported.6–8 The response rate of these therapies ranged from 26% to 63% of selected patients with highly advanced HCCs, suggesting that the remaining patients did not respond to the therapy and died within a few months. To develop more effective combination immunochemotherapy for HCC, in the present study, we examined the cooperative effects of two IFNs: -{alpha} and -ß, with anticancer drugs, on human hepatoma cell lines using growth-inhibitory assays and isobologram analyses. Our results demonstrated that the growth-inhibitory effects of IFN-ß on HCC cells were stronger than those of IFN-{alpha}, and they showed some synergistic effects with 5-FU, CDDP, and DOX.

Both IFN-{alpha} and IFN-ß belong to the same type of IFNs (type I) and interact with the same IFN-{alpha} receptor (IFNAR), but our results showed that their antiproliferative activities were significantly different. IFN-ß suppressed the cell proliferation of the cell lines more potently than IFN-{alpha} (Fig. 1). Consistent with these results, it has been reported that IFN-ß has greater antitumor effects than IFN-{alpha} on melanoma, squamous carcinoma, and breast cancer cells.13–15 One probable mechanism for the different effects may be differences in intracellular signaling, as demonstrated by Shen et al.16 in rat hepatic stellate cells. Other studies also suggested a tighter interaction of IFN-ß than IFN-{alpha} to IFNARs and further dimerization of the IFN-ß-IFNARs complex.17,18 In this regard, it is well known that type I IFNs exert their effects through the specific cell surface receptors, IFNARs, which subsequently activate the JAK/STAT pathway.10 Similar to the differences in their growth-inhibitory effects, previous studies also showed that induction of apoptosis and inhibition of cell cycle by the two IFNs were also different.19–21 Thus, IFN-ß could be a more promising potent agent against human HCC, relative to IFN-{alpha}, when combined with anticancer drugs.

The combination chemotherapy with IFN-{alpha} has been clinically and experimentally investigated for various cancers.22 Our study showed that IFN-ß, similar to IFN-{alpha}, also synergistically inhibited the cell growth of cultured hepatoma cell lines when used with cytotoxic drugs. Among the three agents examined in our study, 5-FU showed the most wide cooperative effect with IFNs (Table 1). One possible mechanism involved in the synergism of 5-FU and IFNs is that the IFNs might increase the amount of active 5-FU metabolites by altering its metabolism or inhibiting over-expression of thymidylate synthase.23,24 In this regard, we previously demonstrated that IFN-{alpha} augments the antitumor effect of 5-FU by inhibiting the progression of the cell cycle, via induction of p27Kip1.25 On the other hand, the biochemical mechanisms of the synergistic effects of IFNs with CDDP or DOX are poorly understood. However, IFNs are demonstrated to delay the cell cycle mainly in the S phase, which may affect the cellular uptake of anticancer drugs.

Our results showed that PLC/PRF/5 cells were more sensitive to IFN treatment with and without anticancer drugs, compared with the other two cell lines. Interestingly, the expression of IFNAR2 was found in one study to correlate with the growth-inhibitory activity of IFN-{alpha}.25 PLC/PRF/5 cells, which were sensitive to IFN therapy, exhibited high expression of IFNAR2, whereas HuH7 and HLE cells expressed lower levels of the receptor (unpublished results, 2003). We have also reported that IFNAR2 was expressed in primary HCCs, but its level in tissues varied widely.26 These findings suggest that the expression of IFNAR2 might be an important factor in predicting the effectiveness of IFNs in combination chemotherapies.

The profiles of the synergistic effects on cell growth inhibition were different between IFN-{alpha} and IFN-ß (Table 1); IFN-ß exhibited a wider synergy in its antiproliferative effect with the anticancer drugs. IFN-{alpha} synergistically suppressed the cell growth of PLC/PRF/5 cells with 5-FU or DOX, whereas IFN-ß inhibited the cell growth of HuH7 and PLC/PRF/5 cells with 5-FU and CDDP. Considered together, these findings suggest that combination chemotherapy with IFN-ß might be useful for advanced HCC including nonresponders to IFN-{alpha} combination therapy. However, further studies in in vitro systems as well as experimental animals are needed to elucidate the underlying mechanism(s) of the different effects of these IFNs.

In conclusion, the results of the present in vitro study suggest that combination chemotherapy with IFN-ß may be effective and useful as an alternative treatment for HCC when combination treatment with IFN-{alpha} is ineffective. For clinical usage of IFN-ß in treatment of patients with HCC, more studies are needed to clarify the optimal dosage and management for any adverse effects of this combination therapy.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the full-text version at www.annalssurgicaloncology.org. They are not available in the PDF version.

This study was supported by a Grant-in-Aid for Scientific Research (13470255) provided by the Ministry of Education, Culture, Sports, Science and Technology, Japan.


   FOOTNOTES
 
Presented at the 56th Annual Cancer Symposium of the Society of Surgical Oncology, Los Angeles, California, March 5–9, 2003.

Our in vitro study demonstrated that interferon (IFN)-ß is more potent in inhibiting the growth of hepatoma cells than IFN-{alpha}, and that both showed synergistic effects with 5-fluorouracil, cisplatin, and doxorubicin.

Received for publication March 6, 2003. Accepted for publication August 25, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  13. Horikoshi T, Fukuzawa K, Hanada N, et al. In vitro comparative study of the antitumor effects of human interferon-{alpha}, ß and {gamma} on the growth and invasive potential of human melanoma cells. J Dermatol 1995; 22: 631–6.[Medline]
  14. Giandomenico V, Vaccari G, Fiorucci G, et al. Apoptosis and growth inhibition of squamous carcinoma cells treated with interferon-{alpha}, IFN-ß and retinoic acid are associated with induction of the cyclin-dependent kinase inhibitor p21. Eur Cytokine Netw 1998; 9: 619–31.[Medline]
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