Vol. 2, 219-224, March 2003
Molecular Cancer Therapeutics
© 2003 American Association for Cancer Research
Efficacy of SCH66336, a Farnesyl Transferase Inhibitor, in Conjunction with Imatinib against BCR-ABL-positive Cells1
Akihiro Nakajima,
Tetsuzo Tauchi2,
Masahiko Sumi,
W. Robert Bishop and
Kazuma Ohyashiki
First Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan [A. N., T. T., M. S., K. O.], and Department of Tumor Biology, the Schering-Plough Research Institute, Kenilworth, New Jersey 07033 [W. R. B.]
2 To whom requests for reprints should be addressed, at First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Phone: 81-3-3342-6111; Fax: 81-3-5381-6651; E-mail: tauchi{at}tokyo-med.ac.jp
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Abstract
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BCR-ABL fusion proteins exhibit elevated tyrosine kinase activity and transforming properties. Genetic and biochemical data suggest that Ras activation plays a central role in leukemogenic transformation by BCR-ABL. Imatinib (Novartis, Basel, Switzerland) is a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL. Although imatinib has shown promise against Ph-positive leukemia in human clinical trials, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for combination chemotherapy to eradicate this disease. In the present study, combined use of a farnesyl transferase inhibitor, SCH66336 (lonafarnib), with the antileukemic agents imatinib, daunorubicin, cytosine arabinoside, or etoposide was investigated by cell proliferation assays. The effects of the combination of SCH66336 and imatinib were also investigated by apoptosis assay and colony-forming assay. In proliferation assays with BCR-ABL-expressing cells, combination of SCH66336 with imatinib or cytosine arabinoside showed enhanced antiproliferative activity, whereas combination of SCH66336 with daunorubicin or etoposide demonstrated an antagonistic effect. The combination of imatinib plus SCH66336 more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. SCH66336 combined with imatinib was shown to induce apoptosis in imatinib-resistant BCR-ABL cells by flow cytometric analysis with an APO2.7 monoclonal antibody. These results indicate that SCH66336 is a promising candidate for use in the treatment of patients with imatinib-resistant, Ph-positive leukemia and that the combination of SCH66336 plus imatinib may be useful to circumvent resistance.
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Introduction
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Most patients with CML,3 some patients with acute lymphocytic leukemia, and a few patients with acute myelogenous leukemia have the Ph chromosome constructed by reciprocal translocation between chromosomes 9 and 22 (1). This translocation results in the production of the BCR-ABL chimeric oncoprotein with enhanced tyrosine kinase activity. Three key biological processes are affected in cells expressing BCR-ABL. BCR-ABL-transformed cells exhibit cell cycle entry in the absence of growth factors, decreased susceptibility to induction of apoptosis after exposure to DNA damage and growth factor withdrawal, and impaired adhesion to extracellular matrix proteins (1).
Because tyrosine kinase activity is the crucial enzymatic activity driving all known functions of the BCR-ABL protein and required for protection from apoptosis by BCR-ABL, targeting this enzyme is an effective approach for therapeutic strategies. Recently, a novel structural entity, imatinib (STI571; Novartis, Basel, Switzerland), a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL, has shown promise against Ph-positive leukemia in human clinical trials (2–4). However, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for combination chemotherapy to eradicate this disease (3, 5).
Oncogenic Ras mutations have been identified in 
30% of human cancers (6) and are among the most common mutations in hematologic malignancies and solid tumors. Ras activation also plays a central role in leukemogenic transformation by BCR-ABL (7). However, cytoplasmic Ras precursor proteins require several modifications to elicit their full activity, and a prerequisite for Ras function is movement to the plasma membrane (8, 9). Farnesyl transferase is necessary for this movement to take place. Farnesylation is the first and most critical step in the post-translation modification of Ras proteins (10). Thus, inhibition of farnesylation is a rational strategy for suppressing the downstream function of Ras proteins.
SCH66336 (lonafarnib) is a p.o. active nonpeptide tricyclic FTI (11–15). Farnesylation of H-ras and K-ras-4B in vitro by purified human FTI is inhibited by SCH66336 with IC50s of 1.9 and 5.2 nM, respectively (11). No inhibition of the related geranylgeranyl protein transferase GGT-1 occurs at SCH66336 concentrations of 
50 µM, confirming the selectivity of this agent for FTI (11). SCH66336 has been shown to possess potent antitumor activity in human cancer cell lines and some hematologic cell lines (11–15). SCH66336 also demonstrates potent antineoplastic activity in nude mice bearing human lung, prostate, colon, and bladder cancer xenografts (11). In addition, SCH66336 potentially blocks the transformed properties of BCR-ABL-positive cells (13–15). Some FTIs, including SCH66336, are currently being tested in Phase I and II clinical trials (9, 16).
In the present study, the combined use of SCH66336 with the antileukemic agents imatinib, DNR, AraC, and VP16 was investigated in vitro. These studies were performed to determine whether these combinations would enhance the activity of SCH66336 and whether they might be useful for circumventing resistance.
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Materials and Methods
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Materials.
SCH66336 was supplied by the Schering-Plough Research Institute (Kenilworth, NJ). The structure of SCH66336 is shown in Fig. 1 (11). Imatinib was kindly provided by Novartis. DNR, AraC, and VP16 were obtained from Sigma Chemical Co. (St. Louis, MO). A stock solution of SCH66336 (10 mM) was prepared in DMSO and maintained at -20°C. DNR, AraC, and VP16 were stored in water at -20°C. Anti-BCR and -ABL monoclonal antibodies were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Anti-SHP-2 monoclonal antibody was obtained from Transduction Laboratories (Lexington, KY).
Cell Lines.
K562 was obtained from the American Type Culture Collection (Manassas, VA). BCR-ABL TF-1 was generated by transfection of the interleukin-3-dependent human acute myelogenous leukemia cell line, TF-1, with a pGD210 vector containing p210 BCR-ABL (B2A2) cDNA as described previously (17). Imatinib-resistant cell lines of BCR-ABL TF-1 (BCR-ABL TF-1-R) were acquired as follows: the BCR-ABL-TF-1 cell line was cultured in McCoy’s 5A medium (supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 100 mg/ml streptomycin) with 0.5 µM imatinib at 37°C for 4 months. Surviving and proliferating cells were plated in 12-cm wells in appropriate growth medium supplemented with 0.3% bact-agar; 0.5 µM imatinib was added, and the cells were incubated for 14 days. Cells were removed from one colony in the dish and maintained in appropriate medium with 0.5 µM imatinib.
Immunoblotting and Immunoprecipitation.
Immunoblotting and immunoprecipitation were performed as described previously (18).
Cell Proliferation Assays in Liquid Culture.
Three milliliters of BCR-ABL TF-1-R cell suspension containing 1 x 105 cells/ml were prepared, and the cell suspension was divided into separate wells of a six-well plate (300,000 cells/well). SCH66336 (1 and 10 µM), 0.1 µM imatinib, or 10 µM SCH66336 combined with 0.1 µM imatinib were then added. The number of cells in each well was then counted every 24 h for 5 days.
Apoptosis Assay.
BCR-ABL TF-1-R cells were cultured with 0.2, 0.5, 1, or 2 µM imatinib alone or in combination with 2 µM SCH66336 at 37°C for 48 h and then stained with FITC-conjugated APO2.7 monoclonal antibody before analysis by flow cytometry (19).
Analysis of Combined Drug Effects.
K562 cells were suspended to a final concentration of 1 x 105 cells/ml in fresh medium, plated in 24-well dishes, and incubated with antileukemic agents alone or in combination with 2 µM SCH66336 at 37°C for 72 h. The antileukemic agents used were 0.05, 0.1, 0.2, 0.3, or 0.4 µM imatinib or 100, 200, or 300 nM DNR, AraC, or VP16. The number of cells in each well was counted by flow cytometry, and the cell numbers were normalized by dividing the number of cells in the absence of antileukemic agents or with SCH66336 alone. The data were plotted as the concentration of antileukemic agents against the percentage inhibition of proliferation. To determine the relationship between the percentage inhibition of proliferation and drug concentration, a best-fit regression line was generated by Microsoft Excel.
Colony-forming Assay.
Bone marrow samples were obtained from two patients with CML-chronic phase treated with hydroxyurea. The growth medium was supplemented with 0.5 µM SCH66336, 0.05 µM imatinib, or a combination of both. Microscopic colonies (erythroid burst-forming units and colony-forming units of granulocytes and macrophages) were counted in triplicate dishes on day 14.
Statistical Analysis.
Comparisons between groups were analyzed using Student’s t test. Differences at P < 0.05 were considered to be statistically significant. The statistical tests were performed using the Microsoft Excel software package for Windows (Brain Power, Inc., Calabashes, CA).
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Results
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Increased Expression of BCR-ABL Protein in Imatinib-resistant, BCR-ABL-transfected Cell Line.
BCR-ABL-TF-1 cells were selectively generated by culture in the presence of gradually increasing concentrations of imatinib. Although nonresistant BCR-ABL-TF-1 cells died in 0.5 µM imatinib, imatinib-resistant BCR-ABL-TF-1 cells proliferated well in the presence of the same concentration. To determine whether imatinib resistance was associated with the alteration of BCR-ABL protein expression described previously (20), immunoblotting was performed on these cell lines (Fig. 2). Compared with BCR-ABL-TF-1 cells, BCR-ABL proteins were significantly overexpressed in BCR-ABL-TF-1-R cells (Fig. 2).
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Fig. 2 Increased expression of BCR-ABL protein in imatinib-resistant, BCR-ABL-transfected cell lines. Cell lysates from indicated cell lines were immunoprecipitated with anti-BCR Ab, then immunoblotted with anti-ABL mAb (top panel). Whole cell lysates were immunoblotted with anti-SHP-2 mAb (bottom panel).
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Effect of SCH66336 on Proliferation Assays.
To assess the effect of SCH66336 on the proliferation rate of BCR-ABL-TF-1-R cells in liquid culture, BCR-ABL-TF-1-R cells were put into medium containing 1 or 10 µM SCH66336 and 0.1 µM imatinib, and cell numbers were counted every 24 h for 5 days (Fig. 3). When BCR-ABL-TF-1-R cells were treated with 1 µM SCH66336 (
), cell growth was inhibited more than when cells were treated with 0.1 µM imatinib only (
). BCR-ABL-TF-1-R cells with 0.1 µM imatinib showed no reduction in proliferation, and cell growth was similar to that of control cells (Fig. 3). In contrast, proliferation of BCR-ABL TF-1-R cells was strongly inhibited by treatment with 10 µM SCH66336 (Fig. 3).
Enhancement of SCH66336-induced Apoptosis.
Despite the profound inhibition of cell proliferation, SCH66336-treated BCR-ABL-TF-1-R cells remained largely viable after 1 week in culture (data not shown). Therefore, the effect of SCH66336 on BCR-ABL-TF-1-R cells was investigated using the APO2.7 monoclonal antibody. BCR-ABL-TF-1-R cells were treated with imatinib only or imatinib in combination with SCH66336 for 48 h and then examined for evidence of apoptosis (Fig. 4). Treatment with 2 µM imatinib and combination with 2 µM SCH66336 significantly increased the proportion of apoptotic cells in comparison with imatinib or SCH66336 alone (Fig. 4).
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Fig. 4 Enhancement of SCH66336-induced apoptosis. BCR-ABL-TF-1-R cells were treated with imatinib only or imatinib in combination with SCH66336 for 48 h and then examined for evidence of apoptosis. Treatment with 2 µM imatinib and combination with 2 µM SCH66336 significantly increased the proportion of apoptotic cells in comparison with imatinib or SCH66336 alone. Similar results were obtained in three independent experiments.
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Analysis of Combined Drug Effects.
DNR, AraC, or VP16 alone or in combination with other agents have been used to treat patients with Ph-positive and -negative leukemia. In recent studies, imatinib showed additive and synergistic effects in combination with some antileukemic agents (21). An investigation was therefore carried out to determine whether SCH66336 could increase the effects of some antileukemic agents, including imatinib, in the CML blast crisis cell line K562. The data are plotted as the concentration of antileukemic agents against inhibition of proliferation, and each antileukemic agent alone (•) is compared with each antileukemic agent in combination with 2 µM SCH66336 (
; Fig. 5A–D). Regression lines generated by Microsoft Excel represent the best-fit relationship between drug concentration and the percentage inhibition of proliferation. R2 values are the square of the correlation coefficient.
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Fig. 5 Analysis of combined drug effects. K562 cells were suspended to a final concentration of 1 x 105 cells/ml in fresh medium and incubated with antileukemic agents alone (•) or in combination with 2 µM SCH66336 () at 37°C for 72 h. The antileukemic agents used were 0.05, 0.1, 0.2, 0.3, or 0.4 µM imatinib (A) or 100, 200, or 300 nM AraC (B), DNR (C), or VP16 (D). The number of cells in each well was counted by flow cytometry. Regression lines generated by Microsoft Excel represent the best-fit relationship between drug concentration and the percentage inhibition of proliferation. R2 values are the square of the correlation coefficient. Similar results were obtained in each of three separate experiments.
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When imatinib was combined with 2 µM SCH66336, the curve showed a substantial shift downward, consistent with increased antiproliferative activity of the drug combination (Fig. 5A). Similarly, with the combination of AraC and SCH66336, the curve was also shifted downward (Fig. 5B). When DNR was combined with 2 µM SCH66336, however, the two curves almost overlapped each other (Fig. 5C), showing that DNR and SCH66336 had no additive combination effect. When VP16 was combined with 2 µM SCH66336, the two curves crossed at 300 nM VP16 (Fig. 5D). There was no additive effect of the combination of VP16 and SCH66336.
Colony-forming Assay.
With the BCR-ABL-TF-1-R and K562 cells, it was confirmed that imatinib and SCH66336 have at least an additive combination effect (Fig. 6). The effect of the combination on bone marrow cells was then investigated. The combination of SCH66336 and imatinib produced a substantial decrease (normalized colony numbers of 30%) in colony formation compared with each agent alone (normalized colony numbers of 70%; Fig. 6). This increased inhibition of colony formation was seen in both erythroid burst- and colony-forming units of granulocytes and macrophage (Fig. 6).
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Fig. 6 Methylcellulose colony-forming assay of CML human primary cells grown in SCH66336 and imatinib. Bone marrow samples were obtained from two patients with CML-chronic phase treated with hydroxyurea. Bone marrow cells were grown in methylcellulose containing the indicated concentrations of SCH66336 and imatinib. Colony counts were assessed on each individual sample at least twice, and the results are presented as average ± SD for colonies counted from triplicate plates under each condition.
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Discussion
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Imatinib is a potent and selective inhibitor of BCR-ABL tyrosine kinase activity and has been shown to have excellent clinical efficacy (2–4). However, the emergence of resistance to imatinib has been recently recognized as a major problem in the treatment of Ph-positive leukemia (5). Several mechanisms of resistance have been identified from in vitro studies with BCR-ABL-positive cell lines. These include amplification or overexpression of BCR-ABL, or increased expression of P-glycoprotein (5, 20, 22). Recent studies with clinical samples from resistant patients have shown that point mutations in the kinase domain of BCR-ABL cause resistance to imatinib (5, 23–26). SCH66336 is a p.o. active, specific inhibitor of farnesyl transferase of H-Ras (11). SCH66336 has been shown to inhibit proliferation of leukemic and solid tumor cells in vitro and in vivo, and this drug is now being tested in clinical trials (9).
In the present study, the combined use of SCH66336 with various antileukemic agents, including imatinib, was investigated. SCH66336 markedly increased the antiproliferative effects of imatinib and AraC in K562 cells (Fig. 5,
A and B). When tested against human primary cells, SCH66336 combined with imatinib strongly suppressed hematopoietic colonies from patients with CML (Fig. 6). Having demonstrated that SCH66336 can increase the efficacy of imatinib and AraC in vitro, additional studies are now warranted to elucidate the mechanisms involved. SCH66336 failed to induce apoptosis in BCR-ABL-transformed cells when used alone and failed to cause changes in the level of apoptotic regulators, such as Bcl-2, BAD, and Bcl-XL (data not shown). Enhancement of apoptosis was observed when SCH66336 was combined with imatinib on BCR-ABL-TF-1-R cells (Fig. 4). SCH66336 has been shown to exert its principal effect on the cell cycle, causing relatively potent G2-M blockage, rather than on the induction of apoptosis (13). Therefore, the cell cycle-dependent effects of these agents are worthy of investigation.
The failure of SCH66336 to potentiate the effect of DNR or VP16 suggests that SCH66336 might affect sensitivity in a drug-specific manner rather than affecting apoptotic cell death. Many lines of evidence point toward multiple farnesylated protein targets when transferase activity is suppressed (9, 27). SCH66336 antagonizes the growth of Ras-dependent and -independent tumor cells in a variety of cell culture and animal models (11). Farnesylation of the H-Ras protein is blocked effectively by SCH66336, but K-Ras and N-Ras proteins are subject to alternative prenylation by becoming substrates for geranyl-geranyl protein transferase (28). Despite alternative prenylation, SCH66336 treatment blocks the growth of K-Ras and N-Ras mutant tumors and is effective against cells transformed by Ras engineered to function independently of farnesylation (11). Therefore, the mechanism of action of this class of compounds appears more complicated than simple inhibition of farnesylation and alteration of the subcellular localization of Ras. Wang et al. (29) reported that SCH66336 is a potent inhibitor of P-glycoprotein and therefore might induce a major form of drug resistance. SCH66336 would be expected to act synergistically with coadministered cancer drugs that are substrates of P-glycoprotein. Indeed, SCH66336 exhibited enhanced antitumor activity when combined with vincristine, paclitaxel, or docetatal (30), all of which are efficient substrates of P-glycoprotein (29). Moreover, SCH66336 may inhibit other export transporters in the avidin-biotin complex transporter superfamily (29). The precise targets, which account for the toxicity of SCH66336 against BCR-ABL-transformed cells, remain to be defined.
In conclusion, the present study has shown that a combination of SCH66336 and imatinib or AraC produced enhanced antiproliferative effects, whereas a combination of SCH66336 and DNR or VP16 produced antagonistic effects against K562 cells (Fig. 5). Although in vitro models are not absolutely predictive of clinical activity, these findings suggest that a combination of SCH66336 and imatinib or AraC may be useful for the treatment of CML or Ph-positive acute lymphocytic leukemia. These findings should provide additional insight into the optimal combination and schedule of SCH66336 for use in clinical practice.
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Footnotes
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1 Supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to T. T.) and the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health Labor and Welfare, Japan (to K. O.), the Promotion and Mutual Aid Corp. for Private School of Japan (to K. O.), and the high-tech research center for intractable disease of Tokyo Medical University from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to K. O.). 
3 The abbreviations used are: CML, chronic myelogenous leukemia; FTI, farnesyl transferase inhibitor; DNR, daunorubicin; AraC, cytosine arabinoside; VP16, etoposide; FPT, farnesyl protein transferase.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9/ 3/02;
revised 11/14/02;
accepted 1/ 7/03.
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Shi, B., Yaremko, B., Hajian, G., Terracina, G., Bishop, W. R., Liu, M., and Nielsen, L. L. The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo.Cancer Chemother. Pharmacol.
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Abstract
Introduction
). Similar results were obtained in three independent experiments.