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Experimental Therapeutics, Preclinical Pharmacology |
Divisions of Cellular and Molecular Biology [J. D., M. B., S. K-R., L. Z. P.] and Experimental Therapeutics [L. Y. Y., M. J. M.], Ontario Cancer Institute, University Health Network, Toronto, Ontario, M5G 2M9 Canada; Departments of Paediatric Laboratory Medicine [H. Y.] and Haematology [M. H. F.], The Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Medical Biophysics [M. B., L. Z. P.], Pharmaceutical Sciences [L. Y. Y., M. J. M.], and Laboratory Medicine and Pathobiology [S. K-R., H. Y.], University of Toronto, Toronto, Ontario, Canada
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tumor cells generally display stalled or arrested differentiation of their normal cellular counterparts (13, 14, 15) . Several biological and clinical features suggest that this differentiation arrest may be reversible because tumor cells can often display a spectrum of maturation along their respective lineages of tissue origin (3 , 14 , 15) . Indeed, differentiation-based therapeutics can restore the regulation of differentiation and enhance the predetermined differentiation programs in tumor cells, often leading to an apoptotic end point (14 , 15) . A hallmark or characteristic of differentiation-based therapeutics is that these agents typically display tumor specificity, targeting distinct subsets of malignancies based on cell lineage (13, 14, 15) . Despite intensive laboratory and clinical research in identifying potential differentiation-based cancer therapeutics, retinoids remain the most active and promising group of agents of this class (16, 17, 18) . The utilization of retinoids, particularly retinoic acid, in therapeutic protocols has been limited because of significant associated toxicity and the acquisition of both systemic and cellular resistance to these agents (13 , 19 , 20) . Because the biological effects of retinoids are mediated through transcriptional regulation by their nuclear receptors (13 , 21) , identification of their gene targets may potentially uncover novel therapeutic approaches circumventing the toxicity and resistance limitations of retinoids (13 , 21) .
To this end, we recently identified the enzyme HMG-CoA3 reductase, the rate-limiting enzyme of the mevalonate pathway, as a retinoic acid-repressed gene and a mediator of the biological effects of retinoic acid (22 , 23) . Mevalonate is a critical intermediate in a complex biochemical pathway, the products of which, including de novo cholesterol, are vital for a variety of key cellular functions affecting membrane integrity, cell signaling, protein synthesis, and cell cycle progression (24) . Lovastatin is a specific, competitive inhibitor of HMG-CoA reductase (25 , 26) , the active open ring form of which can effectively block this critical metabolic pathway, has been used extensively for the treatment of hypercholesterolemia (25 , 26) . Although the biological effects of lovastatin has been attributed to its ability to block HMG-CoA reductase function, a recent report has suggested that the prodrug closed ring form that does not target HMG-CoA reductase is also functional (27) .
The ability of lovastatin to induce growth arrest in a number of tumor-derived cell lines (28) led to its evaluation as a potential anticancer therapeutic agent. In a Phase I clinical trial of 88 patients with solid tumors, where prostate, breast, and central nervous system cancers were evaluated, high doses of lovastatin were well tolerated but did not display any significant anticancer activity (29) . However, a number of recent studies (30, 31, 32) , including our own (23 , 33) , have shown that lovastatin can induce a pronounced apoptotic response in certain tumor types. We have also noted that in the two sensitive tumor types identified in our laboratory, neuroblastoma and acute myeloid leukemia (23 , 33) , lovastatin induces differentiation of these cells prior to apoptosis (34) . This is consistent with our identification of HMG-CoA reductase as a biological mediator of the effects of retinoids (23) . Taken together, these studies suggest that lovastatin, a potential differentiation-based therapeutic that can induce apoptosis, may target a specific and wider subset of tumors and, therefore, should be reevaluated as a therapeutic approach. To test this hypothesis, we determined the sensitivity of a large and varied panel of tumor-derived cell lines to lovastatin-induced apoptosis. We have now extended these studies and have demonstrated that a number of specific cancers are particularly sensitive to the apoptotic effects of lovastatin and include various pediatric malignancies (juvenile monomyelocytic leukemia, rhabdomyosarcoma, and medulloblastoma), squamous cell carcinoma of the cervix, and HNSCC. Moreover, we have shown that the open ring form, and not the prodrug form, of lovastatin is the effective agonist of apoptosis. Thus, targeting HMG-CoA reductase may represent a novel therapeutic approach in the treatment of these cancers.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-MEM (Princess Margaret Hospital
Media Services, Toronto, Ontario, Canada) supplemented with 10% fetal
bovine serum (Sigma Chemical Co., St. Louis). Cells were exposed to
solvent control or to 1–100 µM lovastatin [generously
provided by Merck Research Laboratories, Rahway, NJ; diluted from a 10
mM stock in ethanol prepared as described previously
(28
, 33)
] and processed for MTT, flow cytometric, and
electron microscopic analyses.
MTT Assay.
In a 96-well, flat-bottomed plate (Nunc, Naperville, IL), 
10,000
cells/150 µl of cell suspension were used to seed each well. After 2
days of lovastatin treatment (0–100 µM), 50 µl of a
5-mg/ml solution in PBS of the MTT tetrazolium substrate (ICN, Toronto,
Ontario, Canada) were added and incubated for 6 h at 37°C. The
resulting violet formazan precipitate formed was solubilized by the
addition of 100 µl of a 0.01 M HCl/10% SDS (Sigma)
solution, shaking overnight at 37°C. The plates were then analyzed on
an SLT Labinstruments 340 ATTC ELISA plate reader at 450 nm to
determine the absorbance of the samples.
Flow Cytometry and Electron Microscopy.
Cell cycle parameters were determined by flow cytometry using propidium
iodide labeling of single cells as described previously
(33)
. Single-cell suspensions were labeled with 50 µg/ml
propidium iodide (Sigma), and 106 cells in 100
µl analyzed by flow cytometry. Ten thousand cells were evaluated, and
the percentage of cells in pre-G1 phase was
determined using the Modfit LT program (Verity Software House, Topsham,
ME). For electron microscopy, ultrathin sections of cultured cell
pellets were cut and prepared as described previously
(33)
. Cultured cell pellets were fixed in
phosphate-buffered 2% glutaraldehyde and 1% osmium tetroxide,
dehydrated through acetone, and embedded in epon araldite.
Mass Spectroscopy and HPLC.
Mass spectral analyses were performed at the Mass Spectrometry Facility
of the Biotechnology Service Center at The Hospital for Sick Children
(Toronto, Ontario, Canada). Briefly, electrospray ionization mass
spectrometry was used for the analysis of lovastatin prodrug and the
activated form. Analyses were performed on a model Q-T Mass
Spectrometer using MassLynx Software version 3.2 (Micromass, Montreal,
Ontario, Canada). Samples (10 µl) were introduced into the ionization
source via flow injection (10 µl/min) with 1:1 acetonitrile:water
plus 0.2% (vol/vol) acetic acid. Spectra were collected in the mass
range 50–1500 amu, over a period of about 4 min, at a sampling rate of
1.90/spectrum, with a 0.10-min time lag between two consecutive
spectra. Lovastatin lactone and the open ring acid form were measured
using reversed phase HPLC with solid phase
extraction.4
The internal standard used was cerivastatin, a member of the vastatin
family of HMG-CoA reductase inhibitors. The lower limit of quantitation
of lovastatin was 100 ng/ml.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Using a similar approach to the NCI, we compared the sensitivity of the cell lines used in our survey to lovastatin. Experimental evidence from our previous work with leukemia cell lines and primary cell cultures showed that significant apoptosis after 2 days of exposure to lovastatin was characteristic of MTT values falling to <30% (33) . Evaluating the MTT50 and the MTT30 values (MTT values at 50 and 30% of control) distinguished the sensitive acute myeloid leukemias from the insensitive acute lymphocytic leukemias (33) . On the basis of these data, a S.I. of each cell line was calculated by adding the differences between the calculated means of the MTT50 and MTT30 of all 80 cell lines with the cell line of interest. Each MTT50 and MTT30 value was determined by averaging two independent experiments with six replicates in each experiment. The S.I. for each cell line was then calculated using the following formula S.I. = (MTT50n=1 - meanMTT50n=80) + (MTT30n=1 - meanMTT30n=80). On the basis of our identification of HMG-CoA reductase as a potential mediator of the biological effects of retinoids and the sensitivity of neuroblastomas and acute myeloid leukemias to lovastatin-induced apoptosis (23 , 33) , we included a wide range of retinoid-responsive and nonresponsive cancers in this survey (20 , 41 , 42) . Cell lines derived from juvenile monomyelocytic leukemias, medulloblastomas, rhabdomyosarcomas, prostate carcinomas, melanomas, breast carcinomas, choriocarcinomas, cervical carcinomas, HNSCCs, and renal cell carcinomas were evaluated. Of these, only prostate carcinoma, melanoma, breast carcinoma, and renal cell carcinoma are represented within the NCI screen (39) . Furthermore, we also included four nontransformed fibroblast cell lines.
The sensitivity index of all 80 cell lines, including the leukemic and
neuroblastoma cell lines analyzed in our previous studies (23
, 33)
for comparison purposes, are shown in Table 1
along with their MTT50 and MTT30 values. The S.I. data are also
presented in columnar form to facilitate comparison of lovastatin
sensitivity between the cell lines (Fig. 1)
. The range of the calculated S.I. was from 96 to -97, representing the
most resistant lines to the most sensitive cell lines examined,
respectively. On the basis of our MTT results, the cell lines
segregated into three groups: a nonresponsive group, the MTT50 and
MTT30 values of which were both >100 µM; an intermediate
group, the MTT50 values but not their MTT30 values of which were <100
µM; and a more sensitive group, where both the MTT50 and
MTT30 values fell below 100 µM. Representative MTT
profiles of a number of the cell lines used in this study are shown in
Fig. 2
, A–C, highlighting the differences of the three sensitivity
groups. The difference in responsiveness to lovastatin of acute myeloid
and acute lymphocytic leukemias was well established in our previous
study and validated this analytical approach as a measure of
responsiveness to lovastatin in this cell line series (Fig.
1A). In the pediatric tumor types evaluated (juvenile
monomyelocytic leukemias, medulloblastomas, and rhabdomyosarcomas,),
sensitive, intermediate, and nonresponsive cell lines were evident
within each subtype (Fig. 1
B). The adult solid tumor-derived
cell lines response to lovastatin was linked to tumor type. Although
the majority of prostate and breast carcinomas and melanomas did not
display significant cytotoxicity in response to this agent (Fig. 1
C), the majority of choriocarcinomas, cervical carcinomas,
and HNSCCs were sensitive to lovastatin-induced cytotoxicity (Fig. 1
D). The adult solid tumor subtypes were segregated, based
on their reported responsiveness to retinoic acid. Tumor types that
typically do not display dramatic growth inhibition or differentiation
within therapeutically relevant concentrations of retinoic acid are
grouped in Fig. 1
C, whereas retinoid responsive cancers are
grouped in Fig. 1
D (20
, 41
, 42)
.
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D). The intermediate rhabdomyosarcoma cell line A673
exhibited a weak apoptotic response, as highlighted by the presence of
a pre-G1 peak containing 9.1% of the cells after
a 2-day treatment of 20 µM lovastatin (Fig. 2
D). The sensitive pediatric teratocarcinoma cell line
TERA-2, under identical experimental conditions, showed a significant
apoptotic response highlighted by the presence of a prominent
pre-G1 peak of 46.8% (Fig. 2
D).
Ultrastructural features of apoptotic cell death include chromatin and
cytoplasmic condensation, followed by nuclear and cellular
fragmentation (2
, 5)
. Electron microscopic analysis of
MCF-7 and TERA-2 cell lines either untreated or exposed to 20
µM lovastatin for 2 days clearly highlighted their
distinct responses to lovastatin treatment. Only lovastatin-treated
TERA-2 cells displayed ultrastructural features of apoptosis including
nuclear and cytoplasmic condensation (Fig. 3)
. Therefore, the cytotoxic effects of lovastatin are the result of the
induction of an pronounced apoptotic response that is evident in a
number of tumor types and is absent or muted in the nonresponsive and
the intermediate responsive cell lines analyzed in this study.
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A). The open ring form binds to the active site at a 10x
greater affinity than the natural product, making lovastatin a potent
inhibitor of HMG-CoA reductase (25
, 26) . A recent report
has implicated the lactone form as a potential mediator of the
growth-inhibitory properties of this drug (27)
. We convert
lovastatin to its activated form under basic conditions (NaOH), and the
solution neutralized with the addition of equimolar acid (HCl) as
described previously (28
, 33)
. To determine whether this
treatment had indeed resulted in the formation of the open ring
structure, we evaluated the molecular mass of our lovastatin
preparation before and after chemical activation. Using electrospray
ionization mass spectrometry, the molecular mass of the prodrug was
405.4 Da, as predicted by its chemical structure (Fig. 4
, A
and B). After chemical treatment, the predominant molecular
mass in our preparation was 445.4 Da (Fig. 4
, A and
B). The observed mass coincides with the addition of a water
molecule and a sodium ion as a consequence of opening the ring
structure and the activation protocol, respectively. To quantitate the
extent of activation, HPLC analysis of the prodrug and the activated
forms was performed. As documented previously, the prodrug and
activated forms of lovastatin are distinguishable by HPLC
(27)
. The conversion of the prodrug to the activated form
of lovastatin was shown to be >98% under our activation procedure
(Fig. 4
C).
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A). By contrast, exposure of the TERA-2 cell line to either
preparation induced a prominent cytotoxic response evident by the MTT
assay (Fig. 5
B) as well as morphologically (data not shown).
The prodrug version was slightly less effective than its activated
counterpart. With both the prodrug and activated preparations, addition
of 200 µM mevalonate abrogated the cytotoxic
responses observed (Fig. 5
B). To test whether the open ring
form may be produced spontaneously as a consequence of hydrating the
prodrug form of lovastatin in the media used, we analyzed the HPLC
profile of lovastatin at various time points after the addition of the
prodrug to media. In culture medium, 80% of the prodrug converts to
the activated form within 9 h, with complete conversion occurring
within 24 h (data not shown). Taken together, these results
indicate that the cytotoxic effects induced by lovastatin in this cell
line survey were mediated by the activated form of this drug that
inhibits HMG-CoA reductase activity and function.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The therapeutic potential of lovastatin on the apoptosis-sensitive tumor types identified in our studies were not evaluated in the previous Phase I trial (29) . Indeed, we show here that cell lines derived from the tumor subtypes evaluated in the above Phase I trial did not undergo significant apoptosis in response to lovastatin exposure in vitro. This is consistent with previous reports showing that lovastatin can trigger a cytostatic response in these types of cancer cells (28 , 29) . Furthermore, in a 5-year safety and efficacy study of lovastatin in the treatment of 745 patients with severe hypercholesterolemia, a lower incidence of cancer (14 cases versus 21 expected) was observed (45) . Although this patient population was relatively small, the incidence of breast and prostate carcinomas was as expected; however, no cancers identified as lovastatin sensitive in this study were documented (45) . Using a larger cohort of patients, the effect of prolonged exposure of lovastatin to cancer incidence may determine whether this agent has anticancer and/or chemopreventative capabilities. Therefore, the tumor-specific apoptosis induction as well as the biological properties of the HMG-CoA reductase inhibitors suggests that they are potentially ideal therapeutic agents in the treatment of a specific subset of cancers.
The mechanism of action and the tumor specificity of lovastatin-induced apoptosis remain unclear. The sensitivity to lovastatin-induced apoptosis appears to be cell type dependent and may result from the depletion of critical mevalonate metabolites required for cellular survival in this subset of tumors. Alternatively, nontransformed cells and some tumor-derived cell lines have been shown to respond to the acute depletion of HMG-CoA reductase after lovastatin exposure with growth arrest in the G1 phase of the cell cycle (28) . This suggests that lovastatin triggers a cell cycle checkpoint that may be abolished in the transformation process and lead to increased sensitivity to lovastatin-induced apoptosis in tumors that lack this checkpoint. On the other hand, the level of HMG-CoA reductase activity may determine sensitivity to lovastatin-induced apoptosis; however, our previous work suggests that lovastatin-triggered cytotoxicity is independent of expression levels of this enzyme (23) . Finally, lovastatin may inhibit cell growth by a mechanism independent of this rate-limiting enzyme of the mevalonate pathway (27) . Clearly, understanding the sensitivity and specificity of tumor responsiveness to lovastatin as well as the molecular mechanism of lovastatin-induced apoptosis requires further investigation.
Similar to the effects of other differentiation-based therapeutics, lovastatin induces a pronounced differentiation prior to evidence of overt apoptosis (23 , 33 , 34) and shows tumor specificity. These findings indicate that lovastatin may represent a novel differentiation-based therapeutic approach. Retinoids, derived from mevalonate metabolites, are potent differentiating and growth-inhibitory agents during embryogenesis that have demonstrated efficacy in the prevention and treatment of specific cancers (13 , 41 , 42) . The tumor types responsive to retinoids are generally derived from tissues of mesenchymal, neuroectodermal, hematopoietic, and epithelial origins and include a variety of pediatric tumors, myeloid leukemias, as well as HNSCC and cervical carcinomas (13 , 41 , 42) . This is not surprising because agents that modulate differentiation are generally lineage specific (13) . This spectrum of retinoid-responsive cancers parallels the tumor-derived cell lines that are responsive to lovastatin-induced apoptosis, suggesting a potential mechanistic link.
In this study, we have also demonstrated that apoptosis induced by lovastatin is mediated by the open ring activated form of this drug that targets HMG-CoA reductase. As we propose a new application for HMG-CoA reductase inhibitors, it will be interesting to determine whether the new generation of vastatins will show increased efficacy as anticancer drugs compared with lovastatin. These synthetic compounds have modified structures and/or are in the active open ring conformation and do not require activation (25 , 26 , 46) . Moreover, these synthetic compounds have increased specificity of binding to the intermediate, suggesting elevated activity with relatively low doses in vivo (25 , 26) . Taken together, these vastatins may possess increased bioavailability in vivo and may also represent a therapeutic approach.
Therefore, the tumor-specific apoptosis induction as well as the biological properties of the HMG-CoA reductase inhibitors suggests that they are potentially valuable therapeutic agents in the treatment of these retinoid-responsive cancers. Targeting HMG-CoA reductase may represent a therapeutic alternative in these refractory cancers. An acute myeloid leukemia patient that was treated at our institute using lower lovastatin doses (2 mg/kg/day) for 52 consecutive days demonstrated control of leukemic blast counts that lasted >6 months after cessation of treatment (47) . We are currently conducting Phase I trials for toxicity and efficacy of prolonged low-dose lovastatin treatment in recurrent acute myeloid leukemias, HNSCC, and cervical carcinoma patients as a result of this work.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by The Medical Research Council of
Canada (to L. Z. P.), a joint industry grant from MRC/Apotex, Inc.
(to L. Z. P.), and funds provided by the Canadian Cancer Society to
the National Cancer Institute of Canada (to H. Y.). Fellowship support
from OCI/Amgen and the Charlie Chonacher Research Fund (to J. D.). 
2 To whom requests for reprints should be
addressed, at Division of Cellular and Molecular Biology, Ontario
Cancer Institute, University Health Network, 610 University Avenue,
Toronto, M5G 2 M9 Canada. Phone: (416) 946-2276; Fax: (416) 946-2065;
E-mail: lpenn{at}oci.utoronto.ca
3 The abbreviations used are: HMG-CoA,
3-hydroxy-3-methylglutaryl-CoA; MTT, 3,4,5-dimethyl
thiazlyl-2,2,5-diphenyltetrazolium bromide; HNSCC, head and neck
squamous cell carcinoma; HPLC, high-performance liquid chromatography;
NCI, National Cancer Institute; S.I., sensitivity index.
4 L. Y. Ye and M. J. Moore, manuscript in
preparation.
Received 8/28/00; revised 10/23/00; accepted 10/24/00.
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