Precision therapy to target apoptosis in prostate cancer
Androgen-independent prostate cancer shows limited response to existing systemic therapies. Recent advances in prostate-selective targeting of small molecule inhibitors and bacterial toxins have created opportunities to design a new generation of therapies for advanced prostate cancer. Yet prioritiz...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2014
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| Cite this: | Precision therapy to target apoptosis in prostate cancer / G. Kulik // Experimental Oncology. — 2014. — Т. 36, № 4. — С. 226-230. — Бібліогр.: 48 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859943982845394944 |
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| citation_txt | Precision therapy to target apoptosis in prostate cancer / G. Kulik // Experimental Oncology. — 2014. — Т. 36, № 4. — С. 226-230. — Бібліогр.: 48 назв. — англ. |
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| description | Androgen-independent prostate cancer shows limited response to existing systemic therapies. Recent advances in prostate-selective targeting of small molecule inhibitors and bacterial toxins have created opportunities to design a new generation of therapies for advanced prostate cancer. Yet prioritizing targets for these therapies remain challenging, since multiple mechanisms contribute to the pathophysiology of androgen-independent prostate cancer. This review explores the possibility of targeting the apoptosis regulatory network as most direct approach to efficient treatment of advanced androgen-independent prostate cancer. Key Words: prostate cancer, apoptosis, prostate-selective therapies, PSA-activated pro-drugs, PSMA-targeting toxins.
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| first_indexed | 2025-12-07T16:13:04Z |
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226 Experimental Oncology 36, 226–230, 2014 (December)
PRECISION THERAPY TO TARGET APOPTOSIS IN PROSTATE CANCER
G. Kulik
College of Science, Alfaisal University, Riyadh 11533, Saudi Arabia
Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem 27157, NC, USA
Androgen-independent prostate cancer shows limited response to existing systemic therapies. Recent advances in prostate-selective
targeting of small molecule inhibitors and bacterial toxins have created opportunities to design a new generation of therapies for
advanced prostate cancer. Yet prioritizing targets for these therapies remain challenging, since multiple mechanisms contribute
to the pathophysiology of androgen-independent prostate cancer. This review explores the possibility of targeting the apoptosis
regulatory network as most direct approach to efficient treatment of advanced androgen-independent prostate cancer.
Key Words: prostate cancer, apoptosis, prostate-selective therapies, PSA-activated pro-drugs, PSMA-targeting toxins.
REDUNDANT MECHANISMS
OF ANDROGEN INDEPENDENCE
IN ADVANCED PROSTATE CANCER POSE
CHALLENGE FOR CURRENT THERAPIES
Androgen ablation remains the most effective sys-
temic therapy for advanced prostate cancer, that de-
lays cancer progression 90% of cases. Still, the dise-
ase invariably recurs as androgen-independent
cancer, for which no curative treatment is available.
A critical role of the androgen signaling axis in pros-
tate cancer has been unequivocally demonstrated,
as androgen independence has been connected
with activation of the androgen receptor (AR) despite
androgen ablation the rapy. Mutations in AR that lead
to hypersensitivity to low concentrations of androgen,
or ligand-independent activation of AR have been
identified [1]. New therapies, including abiraterone
acetate (an inhibitor of androgen biosynthesis), and
MDV3100 (an AR antagonist that prevents nuclear
translocation and chromatin binding) can achieve
“complete androgen blockade”. Still, even with com-
plete inhibition of AR signalling, prostate cancer will
eventually progress [2–4].
Broader analysis of androgen independence that
extends beyond the AR axis connected the signaling
pathways from EGFR (HER) family, GPCRs, non-
receptor tyrosine kinases of the Src family, PI3K,
NF-kB, myc, and other regulatory molecules with
advanced androgen-independent prostate cancer [5,
6]. Of these, the PI3K pathway emerged as most
prominent, since mutations leading to its activation
of PI3K pathway were almost invariably detected
by whole-genome sequencing of advanced prostate
cancer [7, 8]. Yet unlike inhibitors of AR signaling that
extend survival of patients with advanced metastatic
prostate cancer up to 16–18 months, inhibitors of other
signaling pathways, including PI3K/mTOR inhibitors
and inhibitors of receptor tyrosine kinases, did not
show significant survival benefit [9–11].
This modest anticancer efficacy is not unique
to prostate cancer. Over the last 20 years, nume-
rous inhibitors of signal transduction enzymes have
been developed. These inhibitors proved invaluable
as experimental tools, yet with the notable exception
of Gleevec, most failed to meet high expectations
to substantially increase patient survival [12]. Several
reasons may account for inefficiency of signal trans-
duction inhibitors in prostate cancer.
First, although complete androgen blockade af-
fects other tissues and has a range of metabolic and
behavioral side effects, prostate cells are the most sen-
sitive to androgen ablation and die first [6]. In contrast,
AR-independent signaling pathways play important
roles in normal physiology of cells and tissues outside
of prostate glands. Therefore, complete inhibition
of these pathways is likely to induce morbid side effects
that limit doses of inhibitors and do not allow complete
inhibition of the signaling pathway in prostate tumors.
Second, there is significant variability between
individual tumors and patients in signaling pathways
that contribute to androgen independence. As a result,
few patients will show the expected response to inhibi-
tors of a specific pathway. When results of all treated
patients are combined in a clinical trial, the differences
between experimental and control groups may still did
not show a statistically significant difference despite
few responsive patients.
Third, analyses of topologies of signal transduction
networks show a substantial level of redundancy, es-
pecially at the “top” at the receptor level [13, 14]. Thus,
even complete inhibition of apical protein kinase or other
signaling molecules will leave alternative pathways intact
and will have little effect on critical effector molecules that
determine the extent of phenotypic response. It appears
that to accomplish an effective anti-tumor response,
several signaling pathways must be inhibited.
Androgen ablation triggers apoptosis in differenti-
ated prostate epithelial cells, yet in advanced andro-
gen-independent prostate tumors, cells no longer die
upon androgen deprivation. In androgen-independent
prostate cancer, the default response of prostate cells
to androgen ablation (i.e. apoptosis) is diverted by other
Submitted: November 5, 2014.
Correspondence: E-mail: gakulik@gmail.com
Abbreviations used: AR — androgen receptor; PSA — prostate-
specific antigen; PSMA — prostate-specific membrane antigen.
Exp Oncol 2014
36, 4, 226–230
Experimental Oncology 36, 226–230, 2014 (December) 227
signaling pathways. Following this logic, targeting
anti-apoptotic signals should complement androgen
ablation therapy. Because apoptosis is most common
evolutionary refined mechanism of elimination of cancer
cells by intrinsic organismal responses and anti-cancer
therapies [15], treatment modalities that aim at apop-
tosis induction are likely to be most efficient.
BAD AND MCL-1 ARE KEY NODES
OF APOPTOSIS REGULATORY NETWORK
What is known about apoptosis regulation in prostate
cancer cells, and how it could be induced most efficient-
ly in prostate tumors? Seminal experiments by Charles
Huggins that showed involution of prostate glands after
androgen ablation in beagles were reproduced in other
animal models with similar results [16]. In 1988, a group
led by John Isaacs reported increased apoptosis in re-
sponse to androgen ablation in rats [17]. Apoptosis
in the prostate gland after androgen ablation therapy
has been confirmed by others, yet the precise mecha-
nism of apoptosis induction remained unknown [18,
19]. As the mechanism of apoptosis regulation became
better understood, the critical role of Bcl2 protein fa-
mily in mitochondrial outer membrane permeability and
commitment to apoptosis was established. Transgenic
mice with increased expression of Bcl2 showed delayed
prostate involution after androgen ablation, suggesting
that common principles of apoptosis regulation were
also true for prostate glands. Still, no convincing data
on changes in Bcl2 family proteins (or other apoptosis-
regulatory molecules) in prostate glands after androgen
ablation were reported [20].
Most studies on the mechanisms of apoptosis
regulation used tissue culture models of cells derived
from prostate tumors: LNCaP, PC3, and DU145 [21].
Of these cell lines, only LNCaP cells remain androgen-
responsive, although they are no longer depend on an-
drogen for survival [22]. Apoptosis regulation in LNCaP
cells was triggered by the loss of PTEN phosphatase,
which negatively regulates the PI3K pathway [23,
24]. As a result, PI3K signaling is constitutively active
and protects LNCaP cells from apoptosis, whereas
inhibition of the PI3K pathway induces apoptosis
in these cells. Extensive analysis of apoptosis regula-
tion in LNCaP and in C42 cells (derived from LNCaP
cells by passaging in immunodeficient mice) identi-
fied several signal transduction pathways that inhibit
apoptosis [13, 25].
These pathways activated by EGFR and GPCR
agonists phosphorylate BAD and protect cells from
apoptosis induced by PI3K inhibitors that triggered
dephosphorylation of BAD. BAD knockout rendered
LNCaP and C42 cells insensitive to apoptosis induction
by PI3K inhibitors and, conversely, expression of BAD
with mutated phosphorylation sites disabled anti-
apoptotic signaling by EGFR, GPCRs, and constitutive-
ly active PI3K [13, 26]. Thus, BAD phosphorylation was
established as a convergence point for anti-apoptotic
signaling pathways in prostate cancer cells. However,
the principal role of BAD was questioned when dyna-
mics of apoptosis induction and BAD dephosphoryla-
tion were compared. In cells treated with PI3K inhibi-
tors, BAD was dephosphorylated within 3–4 hours, but
apoptosis was not detected until 12 hours. In contrast,
the combination of a PI3K inhibitor and a protein
synthesis inhibitor induced apoptosis in 6 hours, yet
dynamics of BAD dephosphorylation in cells treated
with PI3K alone or with a combination of a PI3K inhibitor
and a protein synthesis inhibitor were similar, despite
dramatic differences in timing of apoptosis induc-
tion [27]. These observations prompted the search
for another regulatory molecule that commits prostate
cancer cells to undergo apoptosis.
Earlier reports on interaction preferences between
members of Bcl2 family identified BclXL, Bclw and
Bcl2 as binding partners of BAD, whereas another anti-
apoptotic protein Mcl-1 does not bind BAD [28]. Thus,
in a dephosphorylated state, BAD will bind and neutral-
ize anti-apoptotic effects of BclXL, Bclw, and Bcl2, but
not of Mcl-1. Consequently, in cells that express Mcl-1,
BAD dephosphorylation will have only a mild pro-
apoptotic effect. Mcl-1 is indeed expressed in LNCaP
cells, and treatment with PI3K inhibitors pre dictably
induces only delayed apoptosis, since expression
of Mcl-1 is not affected. In contrast, the combination
of a PI3K inhibitors and a protein synthesis inhibitor
decreased both BAD phosphorylation and Mcl-1 ex-
pression and induced rapid apoptosis [27]. Experi-
ments with shRNA-mediated knockdown of Mcl-1 and
expression of phosphorylation-deficient mutants
of BAD confirmed the essential role of simultaneous
BAD dephosphorylation and Mcl-1 loss in inducing
rapid apoptosis [27].
Mcl-1 is characterized by rapid turnover, with over
80% of protein degraded within 3 hours after protein
synthesis is inhibited. Rapid turnover of Mcl-1 is dic-
tated by ubiquitination-mediated targeting to protea-
somes. Ubiquitination in turn is regulated by phospho-
rylation, which — depending on the specific site — may
either stimulate or inhibit Mcl-1 ubiquitination [29, 30].
Several signaling mechanisms can induce tran-
scription and/or delay Mcl-1 phosphorylation
and increase overall expression of Mcl-1 protein.
The transcriptional factors STAT, CREB, HIF-1, and
TCF, as well as micro-RNA, were implicated in incre-
ased synthesis of Mcl-1 protein. On the other hand,
phosphorylation by the ERK pathway at Thr92 and
Thr163 prolongs Mcl-1 half-life, whereas phosphory-
lation at S169 by GSK3b accelerates degradation.
Thus, signaling pathways emanating from Ras/MAPK,
PI3K/Akt/Gsk3b, GPCR/PKA/CREB and RTK/STAT
could upregulate Mcl-1 expression [30, 31]. Analysis
of BAD phosphorylation identified PKA, RAS/MAPK,
Rac/PAK and PI3K/Akt pathways as responsible for
anti-apoptotic effects of GPCR and EGFR agonists and
loss of PTEN in prostate cells [13, 25, 26]. In summary,
levels of Mcl-1 expression and BAD phosphorylation
are dynamically regulated by overlapping signal trans-
duction pathways, most of which could be inhibited
with existing drugs.
228 Experimental Oncology 36, 226–230, 2014 (December)
The decisive roles of BAD dephosphorylation
and Mcl-1 loss depend on the expression pattern
of other members of the Bcl2 family. For example,
the PC3 prostate cancer cell line, with high expression
of BclXL, shows less apoptosis when BAD dephos-
phorylation and loss of Mcl-1 is induced. Likewise, less
apoptosis is observed in DU145 cells with diminished
expression of BAX. However, when BclXL expression
in diminished and BAX expression is restored, both
cells lines show comparable apoptosis compared
to LNCaP cells. Taken together, these results identify
BAD and Mcl-1 as critical nodes of apoptosis regula-
tory networks, yet their impact on apoptosis depends
on the status of other network members [27].
To translate this information into improved therapies
for advanced prostate cancer, several issues must
be addressed. 1) A systems approach to the analysis
of Bcl2 family proteins is needed, to identify prostate
tumors that may respond to BAD dephosphorylation
and Mcl-1 loss. 2) Signaling pathways that control BAD
phosphorylation and synthesis of Mcl-1 play important
physiological roles in other tissues, and inhibiting these
pathways is likely to induce prohibiting side effects.
A possible way to minimize these side effects is to use
prostate-selective inhibitors. As advanced prostate can-
cer affects mostly older men, preservation of a functional
prostate gland is seldom a priority for these patients [32].
PROSTATE-SELECTIVE THERAPIES
THAT TARGET BAD PHOSPHORYLATION
AND MCL-1
Designers of prostate-selective drugs have uti-
lized two approaches: making a pro-drug activated
by prostate-specific antigen (PSA) cleavage, or linking
active toxins to prostate-specific membrane antigen
(PSMA)-targeting antibodies.
The approach using PSA-activated pro-drugs
pioneered by John Isaacs’ group at Johns Hopkins
University by linking a PSA substrate peptide to thapsi-
gargin, an inhibitor of the Ca2+ channel pump in the en-
doplasmic reticulum. Apoptosis was induced in pros-
tate cancer cell upon 24 h exposure. This approach
was expanded by this group and others by generating
PSA-activated pro-drugs of doxorubicin, vinblastine,
thapsigargin, paclitaxel and proaerolysin [33–38].
However, no pro-drug inhibitors of protein kinases
that can be activated by PSA cleavage and inhibit their
targets only in prostate cells have been made. Since
PI3K is the most frequently activated signaling pathway
in advanced prostate cancer, and our earlier publica-
tions identified PI3K as the major signaling pathway
responsible for constitutive BAD phosphorylation
in prostate cancer cells, it was reasonable to test
whether a PI3K inhibitor pro-drug could be created.
As we have shown recently, LY294002, a widely used
PI3K inhibitor, can be converted into inactive pro-drug
that selectively inhibits PI3K in prostate cancer cell
lines (C42 and LNCaP) cells that secrete PSA, but not
in breast cancer cells, which do not secrete PSA [39].
Future experiments will tell whether more potent in-
hibitors that block PI3K activity at nM concentration
can be generated, and whether these pro-drug PI3K
inhibitors can selectively block PI3K activity in pros-
tate tumors in vivo [40]. Should these experiments
succeed, it will open the door for design of prostate-
selective inhibitors of protein kinases like EGFR, MEK,
PAK or PKA that were identified as upstream kinases
of BAD in prostate cancer cells.
A different approach to producing prostate-tar-
geted drugs is based on fusing toxins to antibodies
against PSMA. The most attention has been generated
by J591 monoclonal antibodies developed by Neil
Bander, now used for both therapeutic and diagnostic
applications [41]. Another set of monoclonal antibo-
dies has been raised by a German group that fused
variable light chain of these antibodies with Pseudo-
monas Exotoxin A [42], which ribosylates elongation
factor 2 and inhibits the translation step of protein
synthesis. A recent analysis of synergistic apoptosis
induction in prostate cancer cells by PI3K and pro-
tein synthesis inhibitors identified Mcl-1 as a critical
regulatory protein responsible for pro-apoptotic ef-
fects of protein synthesis inhibitors in prostate cancer
cells [27, 43].
In summary, both BAD phosphorylation and
Mcl-1 expression are controlled by several convergent
signal transduction pathways [30, 31, 44, 45]. When
Mcl-1 expression is decreased simultaneously with
BAD dephosphorylation (triggered by PI3K inhibition),
robust apoptosis in prostate cancer cells is induced
within 3–4 hours. In contrast, when either BAD phos-
phorylation or Mcl-1 expression alone was inhibited,
apoptosis was evident only after 12–24 hours [27].
Thus, monitoring BAD phosphorylation and Mcl-1 ex-
pression along with immediate targets of signaling in-
hibitors allows prediction of whether prostate-selective
inhibitors will have intended effects. In contrast, moni-
toring only inhibition of immediate targets will have
less predictive power because of multiple redundant
signals that converge on Mcl-1 and BAD.
Analysis of protein expression and phosphorylation
is relatively straightforward for hematopoietic cancers,
yet for solid tumors it poses a substantial challenge.
Repeated biopsies are needed, which is especially
problematic for metastatic tumors. To circumvent the
need for tumor biopsies, surrogate markers have been
proposed. For example, analysis of EGFR phosphory-
lation in hair follicles has been used to monitor efficacy
of EGFR kinase inhibitors [46]. However, this approach
may not be applied for monitoring BAD and Mcl-1,
since signaling pathways that regulate these proteins
are likely different in prostate than in other tissues. Fur-
thermore, considering the high level of hete rogeneity
observed within prostate tumors, several biopsies
may be required to confirm that Mcl-1 expression and
BAD phosphorylation throughout the tumor tissue are
changing. Recently, circulating tumor cells attracted
significant attention as a possible replacement for
tumor biopsies. But it remains unproven whether,
taken out of the microenvironment, tumor cells can
Experimental Oncology 36, 226–230, 2014 (December) 229
adequately represent signaling events inside solid
tumors [47]. One possible alternative is using pri-
mary xenografts of tumor biopsies to select optimal
combination of therapies without subjecting cancer
patients to highly invasive procedures [48]. In fact,
a panel of primary xenografts established from tumor
biopsies could be used to test whether monitoring BAD
phosphorylation and Mcl-1 expression better predicts
a curative response than monitoring immediate targets
of signal transduction inhibitors.
AUTHOR CONTRIBUTIONS
GK conceived and wrote the manuscript.
COMPETING INTERESTS
Author declares no competing interests.
ACKNOWLEDGMENTS
This work was supported by Internal Research
Grant (IRG2014 Project number 4071101011411) from
Alfaisal University.
The author is grateful to Karen Klein (Biomedical
Research Services and Administration, Wake Forest
University Health Sciences) for manuscript editing.
REFERENCES
1. Feldman BJ, Feldman D. The development of an-
drogen-independent prostate cancer. Nat Rev Cancer 2001;
1: 34–45.
2. Tran C, Ouk S, Clegg NJ, et al. Development of a se-
cond-generation antiandrogen for treatment of advanced pros-
tate cancer. Science 2009; 324: 787–90.
3. Fizazi K, Scher HI, Molina A, et al. Abiraterone ac-
etate for treatment of metastatic castration-resistant prostate
cancer: final overall survival analysis of the COU-AA-301 ran-
domised, double-blind, placebo-controlled phase 3 study.
Lancet Oncol 2012; 13: 983–92.
4. Asangani IA, Dommeti VL, Wang X, et al. Therapeutic
targeting of BET bromodomain proteins in castration-resistant
prostate cancer. Nature 2014; 510: 278–82.
5. Kung HJ. Targeting tyrosine kinases and autophagy
in prostate cancer. Horm Cancer 2011; 2: 38–46.
6. Isaacs W, De Marzo A, Nelson WG. Focus on prostate
cancer. Cancer Cell 2002; 2: 113–6.
7. Sarker D, Reid AH, Yap TA, et al. Targeting the PI3K/
AKT pathway for the treatment of prostate cancer. Clin Cancer
Res 2009; 15: 4799–805.
8. Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal
feedback regulation of PI3K and androgen receptor signaling
in PTEN-deficient prostate cancer. Cancer Cell 2011; 19: 575–86.
9. BKM120 in Metastatic Castration-resistant Prostate
Cancer. Available: ClinicalTrials.gov. Novartis Pharmaceuti-
cals. NCT01385293. Accessed November 2014.
10. Study of PI3 Kinase/mTOR Inhibitor BEZ235 Twice
Daily for Advanced Solid Tumors. Available: ClinicalTrials.gov.
Novartis Pharmaceuticals. NCT01343498.
11. Bendell JC, Rodon J, Burris HA, et al. Phase I,
dose-escalation study of BKM120, an oral pan-Class I PI3K
inhibitor, in patients with advanced solid tumors. J Clin Oncol
2012; 30: 282–90.
12. Toniatti C, Jones P, Graham H, et al. Oncology
drug discovery: planning a turnaround. Cancer Discov 2014;
4: 397–404.
13. Sastry KS, Smith AJ, Karpova Y, et al. Diverse anti-
apoptotic signaling pathways activated by vasoactive intestinal
polypeptide, epidermal growth factor, and phosphatidylinositol
3-kinase in prostate cancer cells converge on BAD. J Biol
Chem 2006; 281: 20891–901.
14. Citri A, Yarden Y. EGF-ERBB signalling: towards
the systems level. Nat Rev Mol Cell Biol 2006; 7: 505–16.
15. Llambi F, Green DR. Apoptosis and oncogenesis: give
and take in the BCL-2 family. Curr Opin Genet Dev 2011;
21: 12–20.
16. Huggins C. Endocrine-induced regression of cancers.
In: Nobel Lecture. 1966 edn; 1966.
17. Kyprianou N, Isaacs JT. Activation of programmed cell
death in the rat ventral prostate after castration. Endocrinology
1988; 122: 552–62.
18. McKenzie S, Kyprianou N. Apoptosis evasion: the
role of survival pathways in prostate cancer progression and
therapeutic resistance. J Cell Biochem 2006; 97: 18–32.
19. Buttyan R, Shabsigh A, Perlman H, et al. Regulation
of apoptosis in the prostate gland by androgenic steroids.
Trends Endocrinol Metab 1999; 10: 47–54.
20. de la Taille A, Chen MW, Shabsigh A, et al. Fas antigen/
CD-95 upregulation and activation during castration-induced re-
gression of the rat ventral prostate gland. Prostate 1999; 40: 89–96.
21. Tang DG, Li L, Chopra DP, Porter AT. Extended
survivability of prostate cancer cells in the absence of trophic
factors: increased proliferation, evasion of apoptosis, and
the role of apoptosis proteins. Cancer Res 1998, 58: 3466–79.
22. Berchem GJ, Bosseler M, Sugars LY, et al. Androgens
induce resistance to bcl-2-mediated apoptosis in LNCaP
prostate cancer cells. Cancer Res 1995; 55: 735–8.
23. Vlietstra RJ, van Alewijk DC, Hermans KG, et al.
Frequent inactivation of PTEN in prostate cancer cell lines
and xenografts. Cancer Res 1998; 58: 2720–3.
24. Carson JP, Kulik G, Weber MJ. Antiapoptotic signaling
in LNCaP prostate cancer cells: a survival signaling pathway
independent of phosphatidylinositol 3’-kinase and Akt/protein
kinase B. Cancer Res 1999; 59: 1449–53.
25. Sastry KS, Karpova Y, Prokopovich S, et al. Epi-
nephrine protects cancer cells from apoptosis via activation
of cAMP-dependent protein kinase and BAD phosphorylation.
J Biol Chem 2007; 282: 14094–100.
26. Sastry KS, Karpova Y, Kulik G. Epidermal growth
factor protects prostate cancer cells from apoptosis by induc-
ing BAD phosphorylation via redundant signaling pathways.
J Biol Chem 2006; 281: 27367–77.
27. Yancey D, Nelson KC, Baiz D, et al. BAD dephos-
phorylation and decreased expression of MCL-1 induce rapid
apoptosis in prostate cancer cells. PLoS One 2013; 8: e74561.
28. Chen L, Willis SN, Wei A, et al. Differential targeting
of prosurvival Bcl-2 proteins by their BH3-only ligands allows
complementary apoptotic function. Mol Cell 2005; 17: 393–403.
29. Zhong Q, Gao W, Du F, et al. Mule/ARF-BP1, a BH3-
only E3 ubiquitin ligase, catalyzes the polyubiquitination
of Mcl-1 and regulates apoptosis. Cell 2005; 121: 1085–95.
30. Thomas LW, Lam C, Edwards SW. Mcl-1; the molecular
regulation of protein function. FEBS Lett 2010; 584: 2981–9.
31. Akgul C. Mcl-1 is a potential therapeutic target in mul-
tiple types of cancer. Cell Mol Life Sci 2009; 66: 1326–36.
32. McConnell JD. Androgen ablation and blockade
in the treatment of benign prostatic hyperplasia. Urol Clin
North Am 1990; 17: 661–70.
33. Brady SF, Pawluczyk JM, Lumma PK, et al. Design
and synthesis of a pro-drug of vinblastine targeted at treatment
of prostate cancer with enhanced efficacy and reduced systemic
toxicity. J Med Chem 2002; 45: 4706–15.
34. DeFeo-Jones D, Brady SF, Feng DM, et al. A pros-
tate-specific antigen (PSA)-activated vinblastine prodrug
230 Experimental Oncology 36, 226–230, 2014 (December)
selectively kills PSA-secreting cells in vivo. Mol Cancer Ther
2002; 1: 451–9.
35. Denmeade SR, Jakobsen CM, Janssen S, et al. Prostate-
specific antigen-activated thapsigargin prodrug as targeted the-
rapy for prostate cancer. J Natl Cancer Inst 2003; 95: 990–1000.
36. Khan SR, Denmeade SR. In vivo activity of a PSA-
activated doxorubicin prodrug against PSA-producing human
prostate cancer xenografts. Prostate 2000; 45: 80–3.
37. Williams SA, Merchant RF, Garrett-Mayer E, et al.
A prostate-specific antigen-activated channel-forming toxin
as therapy for prostatic disease. J Natl Cancer Inst 2007;
99: 376–85.
38. Elsadek B, Graeser R, Esser N, et al. Development
of a novel prodrug of paclitaxel that is cleaved by prostate-
specific antigen: an in vitro and in vivo evaluation study. Eur
J Cancer 2010; 46: 3434–44.
39. Baiz D, Pinder TA, Hassan S, et al. Synthesis and charac-
terization of a novel prostate cancer-targeted phosphatidylinosi-
tol-3-kinase inhibitor prodrug. J Med Chem 2012; 55: 8038–46.
40. Welker ME, Kulik G. Recent syntheses of PI3K/Akt/
mTOR signaling pathway inhibitors. Bioorg Med Chem 2013;
21: 4063–91.
41. Bander NH, Nanus DM, Milowsky MI, et al. Tar-
geted systemic therapy of prostate cancer with a monoclonal
antibody to prostate-specific membrane antigen. Semin Oncol
2003; 30: 667–76.
42. Buhler P, Wolf P, Elsasser-Beile U. Targeting the pros-
tate-specific membrane antigen for prostate cancer therapy.
Immunotherapy 2009; 1: 471–81.
43. Baiz D, Hassan S, Choi YA, et al. Combination
of the PI3K inhibitor ZSTK474 with a PSMA-targeted im-
munotoxin accelerates apoptosis and regression of prostate
cancer. Neoplasia 2013; 15: 1172–83.
44. Morel C, Carlson SM, White FM, et al. Mcl-1 inte-
grates the opposing actions of signaling pathways that mediate
survival and apoptosis. Mol Cell Biol 2009; 29: 3845–52.
4 5 . Per ci ava l l e R M , O p f er m a n J T. D el v i n g
de eper: MCL-1’s contributions to normal and cancer biology.
Trends Cell Biol 2013; 23: 22–9.
46. Albanell J, Rojo F, Averbuch S, et al. Pharmacody-
namic studies of the epidermal growth factor receptor inhibi-
tor ZD1839 in skin from cancer patients: histopathologic and
molecular consequences of receptor inhibition. J Clin Oncol
2002; 20: 110–24.
47. Danila DC, Fleisher M, Scher HI. Circulating tumor
cells as biomarkers in prostate cancer. Clin Cancer Res 2011;
17: 3903–12.
48. Lin D, Wyatt AW, Xue H, et al. High fidelity patient-
derived xenografts for accelerating prostate cancer discovery
and drug development. Cancer Res 2014; 74: 1272–83.
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| id | nasplib_isofts_kiev_ua-123456789-145372 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-07T16:13:04Z |
| publishDate | 2014 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Kulik, G. 2019-01-21T08:29:32Z 2019-01-21T08:29:32Z 2014 Precision therapy to target apoptosis in prostate cancer / G. Kulik // Experimental Oncology. — 2014. — Т. 36, № 4. — С. 226-230. — Бібліогр.: 48 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145372 Androgen-independent prostate cancer shows limited response to existing systemic therapies. Recent advances in prostate-selective targeting of small molecule inhibitors and bacterial toxins have created opportunities to design a new generation of therapies for advanced prostate cancer. Yet prioritizing targets for these therapies remain challenging, since multiple mechanisms contribute to the pathophysiology of androgen-independent prostate cancer. This review explores the possibility of targeting the apoptosis regulatory network as most direct approach to efficient treatment of advanced androgen-independent prostate cancer. Key Words: prostate cancer, apoptosis, prostate-selective therapies, PSA-activated pro-drugs, PSMA-targeting toxins. This work was supported by Internal Research Grant (IRG2014 Project number 4071101011411) from Alfaisal University. The author is grateful to Karen Klein (Biomedical Research Services and Administration, Wake Forest University Health Sciences) for manuscript editing. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Precision therapy to target apoptosis in prostate cancer Article published earlier |
| spellingShingle | Precision therapy to target apoptosis in prostate cancer Kulik, G. Reviews |
| title | Precision therapy to target apoptosis in prostate cancer |
| title_full | Precision therapy to target apoptosis in prostate cancer |
| title_fullStr | Precision therapy to target apoptosis in prostate cancer |
| title_full_unstemmed | Precision therapy to target apoptosis in prostate cancer |
| title_short | Precision therapy to target apoptosis in prostate cancer |
| title_sort | precision therapy to target apoptosis in prostate cancer |
| topic | Reviews |
| topic_facet | Reviews |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/145372 |
| work_keys_str_mv | AT kulikg precisiontherapytotargetapoptosisinprostatecancer |