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Experimental Therapeutics, Preclinical Pharmacology |
Department of Pediatrics, Steele Memorial Children’s Research Center, University of Arizona, Tucson, Arizona 85724 [R. B., E. J. P., L. W.]; Arizona Cancer Center, University of Arizona, Tucson, Arizona [G. D. P-M., C. W. T.]; Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan [S. A.]; and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390 [I. J. B.]
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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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Distinct from their inhibition of proliferation-associated signaling pathways, however, HBAs have also been shown to act as potent inducers of the cellular heat shock or stress response (20, 21, 22) . Recent mechanistic work in vitro has demonstrated that Hsp90 forms complexes with the major transcriptional regulator of the vertebrate heat shock response, HSF1 (23 , 24) . The Hsp90 association with HSF1 appears to maintain HSF1 in a repressed, transcriptionally inactive form, and HBAs are thought to initiate the stress response in a novel, nonproteotoxic manner by disrupting Hsp90-HSF1 interaction (25) . Whether HBA-mediated induction of a stress response in this novel way contributes to the potent cytotoxic activity of these compounds or acts in a cytoprotective fashion to limit cell damage after drug exposure is unknown. To address this issue, we used transformed fibroblasts derived from either wild-type or homozygous HSF1 knock-out mice and performed quantitative dose-response analyses of cell proliferation/survival after exposure to HBA and conventional chemotherapeutic agents. To assess the relevance of these in vitro findings to the therapeutic application of HBAs, we then examined Hsp induction in tumor-bearing mice after systemic administration of an HBA. Our results indicate that induction of the heat shock response by HBAs will be an important consideration as the toxicity and activity of these drugs are explored in current and upcoming clinical trials.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Analysis of HSF1-regulated Transcription.
NIH 3T3 cells were transfected with a reporter construct encoding
EGFP (Clontech, Palo Alto, CA) under the transcriptional control of a
400-bp promoter fragment derived from the HSP70B gene
(kindly provided by T. Tsang, University of Arizona). Stable
transformants were selected in G418 (geneticin, 500 µg/ml; Life
Technologies, Inc.) for 3 weeks. Cells were heat shocked (42°C for 30
min) to induce EGFP expression and fluorescence activated cell sorting
was performed 24 h later to isolate a population of cells
displaying a robust reporter response to heat stress. To assess
reporter activation by drugs, these stably transfected, sorted 3T3
cells were exposed to GA or cadmium, followed by wash-out and refeeding
with drug-free medium. Cells were fixed 24 h later with 4%
paraformaldehyde and viewed using a Zeiss Axiovert epifluorescence
microscope and FITC filter set. Images were acquired electronically on
a SenSys cooled HCCD camera (Photometrics, Tucson, AZ) and processed
using Adobe Photoshop software (San Jose, CA).
Drug-mediated Hsp Induction.
To examine the effects of drug treatment on cellular protein synthesis,
replicate dishes of wild-type and HSF1 knock-out fibroblasts
were rinsed with methionine/cysteine-free DMEM supplemented with 10%
dialyzed fetal bovine serum and incubated at 37°C for 2 h
in drug-containing medium, followed by addition of
[35S]methionine/[35S]cysteine
(Translabel, 10.5 mCi/ml; ICN, Costa Mesa, CA) to yield 100 µCi/ml.
Incubation was continued for an additional hour. Cell lysates were then
prepared and analyzed by SDS-PAGE, as described previously
(12)
. To examine drug effects on the synthesis of specific
Hsps, IP was performed from metabolically labeled cell lysates using
antibodies to Hsp90 and Hsp70, as described previously
(17)
. To evaluate total cellular levels of specific Hsps
in drug-treated cells, replicate dishes of wild-type and
HSF1 knock-out fibroblasts were lysed in nonionic detergent
buffer, and immunoblotting was performed using 50 µg of total
protein/sample, as described previously (17)
.
Chemiluminescent substrate and exposure to Kodak XAR-5 film were used
for detection. Multiple exposure times were evaluated for each blot to
ensure that the band intensities observed were within the dynamic
response range of the film.
Quantitation of Cell Survival/Proliferation.
To assess the role of HSF1 in modulating drug sensitivity, a
semiautomated assay of relative viable cell number based on the
mitochondrial reduction of MTT (Sigma) was used as described previously
(27)
. Briefly, HSF1 knock-out and wild-type
fibroblasts were plated in 96-well plates (2.5 x
103
cells/well) and treated 24 h after
plating with varying concentrations of 17AAG, KF 58333, doxorubicin, or
CDDP. After 24 h incubation at 37°C, the medium was removed, and
cells washed twice with fresh medium and then incubated for an
additional 48 h in drug-free medium. MTT (500 µg/ml) was then
added to each well, and plates were incubated for 2 h at 37°C.
Medium was removed, and DMSO (150 µl/well) was added, followed by
gentle agitation for 10 min in the dark. Absorbance was determined at
540 nm, and values for drug-treated wells were compared with those for
vehicle-treated control wells assayed on the same plate. All
determinations were performed in triplicate, and each experiment was
repeated three times. Results were calculated as a percentage of
control absorbance, and dose-response curves were compared using a
two-way ANOVA with P < 0.05 considered significant.
Heat Shock Induction in Vivo.
SCID mice (University of Arizona Breeding Colony) were treated
with 75 mg/kg 17AAG formulated in DMSO and injected i.p. daily for 2
days. Animals were sacrificed 24 h after the last drug dose, and
organs were harvested. Snap-frozen brain, liver, and lung tissues were
pulverized, and cytosolic extracts were prepared in hypotonic lysis
buffer (pH 8.2) containing 10 mM HEPES, 1 mM
EDTA, and 10 mM sodium molybdate. Lysates (50 µg/lane)
were fractionated by 7.5% SDS-PAGE, and immunoblotting was performed
using anti-Hsp72 primary antibody. Additional SCID mice were inoculated
s.c. with MCF7 human breast cancer cells, as described previously
(28)
. Tumor-bearing mice received i.p. injections of 17AAG
at dose levels of either 50 or 100 mg/kg daily for 4 consecutive days.
Control mice received i.p. injections of an equal volume of DMSO. Mice
were sacrificed, tumors were resected 18 h after final drug
injection, and tumors were analyzed for Hsp72 levels as above. All
experiments involving mice were carried out under protocols approved by
the University of Arizona Institutional Animal Care and Use Committee.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B). A strong but somewhat less intense signal was observed
when cells were exposed briefly to GA (Fig. 1
A), indicating
that HBA treatment transcriptionally activated the reporter construct.
In comparison, cells treated only with drug diluent demonstrate minimal
signal (Fig. 1
C), consistent with autofluorescence.
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A, cells were exposed to KF58333 or the conventional
DNA-damaging agent doxorubicin. Autoradiography of total lysate
prepared from wild-type cells treated with KF58333 demonstrated a clear
increase in the levels of newly synthesized proteins with apparent
molecular sizes of 90 and 70 Mr,
presumably representing Hsp90 and Hsp70 isoforms. No such increases
were seen with doxorubicin, and no increases were seen in
HSF-/- cells treated with either agent.
Immunoprecipitations from radiolabeled lysates with anti-Hsp70 antibody
were performed to verify the identity of the 70 kDa bands seen in Fig. 2
A as Hsp70 isoforms. Two bands are evident in these
precipitations, one representing Hsp73 (also known as Hsc70), the major
constitutive Hsp70 isoform and the other Hsp72, a highly inducible
isoform that is expressed at very low levels under nonstress conditions
in most tissues (Fig. 2
B). Little variation was seen in
Hsp73 signal between samples, but both KF58333 and 17AAG elicited a
marked increase in the level of Hsp72 in cells with normal HSF1
function. Isogenic cells without HSF1 displayed minimal increases.
Consistent with total lysate data presented in Fig. 2
A,
increased Hsp72 synthesis was not evident in precipitations using
lysate from either wild-type or knock-out cells treated with
doxorubicin or DMSO vehicle. The absence of signal in the control IP
lanes confirms the specificity of the immunoprecipitation conditions
used.
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A, wild-type cells were exposed to GA or incubated at 42°C
for 30 min, and lysates were prepared 24 h later to compare the
Hsp levels induced by these two stimuli. HSF1 knock-out
cells were not examined because, as reported previously
(26)
, these cells fail to induce Hsp synthesis, even after
incubation at 43°C for 30 min. Although exposure of wild-type cells
to GA resulted in substantial Hsp72 induction compared with control, we
found that the level of detectable Hsp72 was considerably greater after
moderate heat shock. We next prepared lysates from wild-type and
knock-out cells 18 h after treatment with several HBAs and
conventional chemotherapeutic agents. Small but consistent differences
in the levels of Hsp72 and Hsp90 were observed between the two cell
types under control conditions (DMSO vehicle alone), perhaps reflecting
a role for HSF1 in regulating basal Hsp expression or a response of
cells with intact HSF1 function to the mild stresses inherent in cell
culture (Fig. 3
, B and C). After exposure to
17AAG, RD, and KF58333, a marked increase in Hsp72 level and a less
apparent increase in Hsp90 level were seen in wild-type cells but not
in HSF1 knock-out cells. No increase in Hsp72 levels over
their respective control levels were seen in either cell type, however,
after exposure to conventional cytotoxic agents. Neither an
intercalator/topoisomerase inhibitor (doxorubicin), nor an alkylator
(CDDP), nor an antimetabolite (5-fluorouracil) caused detectable
increases in Hsp levels in these cells under conditions demonstrated by
quantitative dose-response analysis to reduce proliferation/survival by
at least 50% (see below; Fig. 4
, C and D). These data demonstrate that the
ability of HBAs to induce a heat shock response requires HSF1 function,
and that induction of this response is a biological property of these
agents distinct from that of DNA-targeted chemotherapeutics.
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, dose-response data were obtained two
days after a 24-h exposure to various drug concentrations. Knock-out
cells were significantly more sensitive to 17AAG (Fig. 4
A)
and KF58333 (B) than their wild-type counterparts, as
determined by two-way ANOVA (P < 0.0001). In contrast,
no statistically significant difference was observed between the two
cell types when treated with CDDP (Fig. 4
C;
P > 0.6) and doxorubicin (Fig. 4
D;
P > 0.37).
HBA Treatment Induces a Heat Shock Response in Vivo.
To examine the clinical implications of our in vitro
findings, we assessed the effects of systemic 17AAG exposure on normal
tissues and tumor xenografts in SCID mice. After IP administration of
17AAG or an equal volume of DMSO to non-tumor-bearing mice, organs were
harvested. Elevated levels of Hsp72 were found in liver and lung from
animals treated with 17AAG, as shown in Fig. 5
A. Surprisingly, brain tissue from animals treated with the
HBAs showed no increase in Hsp72 level. We also assessed heat shock
induction by 17AAG in established human breast tumor xenografts.
Systemic drug treatment of tumor-bearing mice at a well-tolerated dose
induced a readily detected increase in tumor hsp72 level compared with
that seen in tumors from DMSO-treated control mice (Fig. 5
B).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and at
the translational level using [S35]methionine
labeling (Fig. 3)
and Western blotting (Fig. 4)
. Consistent with
previous reports using herbimycin A (21
, 22)
but in
contrast to a recent report by Ali et al. (33)
,
we found that HBA exposure resulted in robust induction of Hsp
expression. Ali et al. (33)
made use of
Xenopus oocytes into which a heat-inducible reporter
construct was microinjected. Whether the discrepancy between their
results and ours reflects a fundamental difference in heat shock
regulation between frogs and mammals or a technical difference in the
reporter constructs and transfection techniques used is not clear. Our findings indicate that exposure of cells to concentrations of HBAs that cause changes in survival and proliferation do not induce Hsp expression to the same extent as that seen in cells exposed to heat or heavy metals. Compared with HBAs, these relatively nonspecific stressors may stimulate more robust responses because they activate not only HSF-1 but additional cofactors such as HSF-2 (30) . In addition, these physical agents have been shown to affect attenuators of the heat shock response such as Hsp70-family chaperones, which may allow them to generate a more prolonged, exaggerated response than that seen with the HBAs, which act only on Hsp90 (34) . Alternatively, HBAs are known to inhibit the activity of multiple kinases involved in signal transduction. Perhaps exposure to HBAs stimulates HSF1 trimer formation but also impairs the activity of the as yet unidentified kinase(s) that are required to inducibly phosphorylate HSF1 and render it active. Additional work comparing the effects of heat, nonsteroidal anti-inflammatory drugs, and HBAs on HSF1 phosphorylation may prove useful in identifying the kinase(s) involved in regulating HSF1 function.
Mechanistically, it is perhaps not surprising that HSF1 knock-out cells were more sensitive to the cytotoxic action of HBA than wild-type cells. Hsp90 function is known to be essential for survival in eukaryotes (35) . The ability of wild-type cells to increase Hsp90 levels probably allowed them to restore normal Hsp90 function more effectively than knock-out cells after drug exposure, thus leading to their enhanced survival. The ability of normal cells and tissues to up-regulate Hsp90 levels in the face of HBA exposure may explain why the compounds are less toxic than might be expected (given the essential nature of Hsp90 function), and this ability suggests that at noncytotoxic doses, the compounds may prove useful as "biological response modifiers" for therapeutic manipulation of the stress response in diseases involving processes such as inflammation or ischemia. It has been suggested that the benzoquinone ansamycins may not act primarily through modulating Hsp90 function but rather by inducing more general oxidative damage (36) or alkylating target proteins such as src kinase (37 , 38) . Our data argue strongly against these possibilities: (a) we found that RD and its derivative KF58333 induce a heat shock response, and yet these compounds lack the quinone ring responsible for proposed free radical formation (see Ref. 4 for structures); (b) HSF1-deficient cells were more sensitive to HBAs than wild-type cells, but no such difference was seen with another redox active, quinone-containing agent, doxorubicin, which does not interact with Hsp90.
Increased levels of certain Hsps have been reported to confer
drug resistance to cancer cells (39
, 40)
. Whether the heat
shock response, per se, is cytoprotective in the face of
exposure to conventional genotoxic chemotherapeutics has remained
unclear. Our data with transformed cells in which the heat shock
response has been disabled indicate that this response does not play a
major role in modulating the cytotoxicity of several distinct classes
of chemotherapeutic agents. Although there are obvious limitations to
an in vitro model involving rodent cells, the cell lines
used in the experiments reported here were transformed with E6 and E7,
rendering them functionally p53 and Rb deficient, as is the case with
many human cancers. Our findings have several other important
implications for the clinical application of HBA as anticancer drugs:
(a) given the cytoprotective effect of the heat shock
response in cells exposed to HBA (Fig. 4)
, it may be important to
administer these agents in a pulsed fashion, with a sufficient interval
between exposures to allow drug-induced heat shock responses to
extinguish; (b) we did not detect an increase in Hsp72
levels in brain tissue after administration of 17AAG (Fig. 5)
or
KF58333 (not shown). Either these drugs do not penetrate the blood
brain barrier or as suggested by others, induction of the heat shock
response is regulated differently in neurons compared with other cells
(41)
. If the latter is the case, neurotoxicity may be an
important potential complication when administering these agents to
patients; and (c) the finding that HBAs induce a measurable
change in cellular Hsp levels suggests that this biological response
will prove a useful pharmacodynamic end point for therapeutic
monitoring in vivo. In fact, measurement of Hsp72 levels in
tumor tissue and peripheral blood lymphocytes has been incorporated
into the design of the Phase I clinical trials of 17AAG that have now
begun in patients with refractory malignancies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported in part by NIH Grants
CA69537 and CA09213 and funds from the Caitlin Robb Foundation and Mel
and Enid Zuckerman Foundation. 
2 To whom requests for reprints should be
addressed, at Pediatric Hematology/Oncology, Steele Memorial
Children’s Research Center, University of Arizona, 1501 North Campbell
Avenue, Tucson, AZ 85724. Phone: (520) 626-4851; Fax: (520) 626-4220;
E-mail: whitelj{at}peds.arizona.edu
3 The abbreviations used are: Hsp, heat shock
protein; RD, radicicol; GA, geldanamycin; HBA, Hsp90-binding agent;
HSF1, heat shock factor 1; 17AAG, 17-allylaminogeldanamycin; CDDP,
cisplatin; EGFP, enhanced green fluorescent protein; IP,
immunoprecipitation; MTT,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.
Received 12/ 9/99; revised 5/ 5/00; accepted 5/10/00.
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REFERENCES |
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