Page 291 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

270 PART III Therapeutic Modalities for the Cancer Patient

enhance apoptosis in tumor and endothelial cells, 370,374–376 before a standard dose of DOX in tumor-bearing dogs, at dosages
and directly inhibit tumor cell proliferation. 375,377–379 Consis- sufficient to enhance histone acetylation in tumor and periph-
eral blood mononuclear cells, but not associated with toxicity or
tent with its role as a transcriptional repressor, inhibition of
VetBooks.ir HDACs has been shown to induce differentiation in thyroid apparent potentiation of DOX’s adverse effects. 392
380–384
and prostate cancer, neuroblastoma, and the leukemias.
HDAC inhibition enhances the in vitro and in vivo efficacy The Proteasome
of multiple standard cytotoxic therapies, antibodies and small
molecules. 367,370,376,385–393 The abundance of cellular proteins is tightly controlled at the
Two HDAC inhibitors, vorinostat (SAHA, Zolinza, levels of both production and destruction. Protein production
Merck) and romidepsin (FK228, Istodax, Celgene), have been can be modified at the transcriptional and posttranscriptional
approved by the FDA for the treatment of cutaneous T-cell lym- level, and therapies based on these approaches are relatively abun-
phoma, 394–396 and a large number of additional agents are in dant. Until relatively recently, little attention had been paid to
intermediate- to late-stage clinical trials. A number of studies the manipulation of protein degradation as a therapeutic modal-
are being conducted evaluating HDAC inhibitors for various ity. The ubiquitin–proteasome pathway (UPP) is responsible for
other hematologic and solid tumors, and early studies combin- the degradation of the majority of intracellular proteins, and is
ing these drugs with other targeted and cytotoxic therapies have responsible for the regulation of many proteins with key roles in
been reported. 397–400 cancer.
Recent in vitro studies have demonstrated potent induction The 26S proteasome is a large multiprotein complex contain-
of histone acetylation, growth inhibition, and induction of apop- ing ubiquitin recognition domains, which bind ubiquitinated
tosis in a variety of canine tumor cell lines treated with either proteins tagged for degradation, and proteolytic domains with
vorinostat or the novel HDAC inhibtior OSU-HDAC42 (AR- trypsin-like, chymotrypsin-like, and caspase-like activity, which
42) 401,402 ; and inhibition of canine prostate cancer metastasis to degrade proteins into short polypeptide sequences. 405 It is respon-
bone was observed after AR-42 treatment in a murine xenograft sible for the degradation of a variety of proteins responsible for
model. 403 Synergy between vorinostat and the DNMT inhibi- cell-cycle regulation, angiogenesis, apoptosis, and chemotherapy
tor zebularine has been observed in canine OSA cell lines. 358 The and radiation sensitivity (Table 15.3). 405–407
commercially available anticonvulsant drug VPA can function Tumor cells are generally more sensitive to the effects of pro-
as an HDAC inhibitor, and is capable of inhibiting tumor cell teasome inhibition than are normal cells. Various studies have
invasion, P-glycoprotein expression, proliferation and angiogen- demonstrated a 3- to 40-fold increase in susceptibility to pro-
esis, and enhancing chemosensitivity. 404,367,381 VPA was recently teasome inhibitor-associated apoptosis when comparing tumor
shown to enhance the efficacy of DOX in canine OSA cell lines cells with corresponding normal tissues. 407–411 The mechanisms
in vitro, and to synergize with DOX in a canine OSA xenograft. 391 for this differential sensitivity are unclear, but proliferating cells
A recent study demonstrated that VPA could be administered generally appear more sensitive than do quiescent cells. 405,407 In

TABLE 15.3 Molecular Targets and Consequences of Proteasome Inhibition
Process Proteins Degraded by Proteasome Cellular Consequences
NFκB activation IκB Accumulation of IκB inhibits nuclear translocation and activity of
NFκB, leading to decreased proliferation, survival, invasion,
angiogenesis.
Apoptosis p53, Bax, tBid, Smac, JNK, Noxa Accumulation of these proteins directly or indirectly promotes
apoptosis through various pathways.
Cell cycle regulation p21, p27, other CDK inhibitors, cyclins, p53 Accumulation of CDK inhibitors can cause cell-cycle arrest and
apoptosis. The increased expression of multiple cyclins can
send contradictory signals to the cell resulting in apoptosis.
Signal transduction MKP-1 phosphatase Accumulation dephosphorylates p44/42 MAP kinase, leading to
decreased MAPK pathway signaling, proliferation, survival,
+/– angiogenesis.
Oncogenic transformation c-Fos, c-jun, c-myc, N-myc Unclear how overabundance of these proteins exerts an
antitumor effect.
Unfolded protein response Various damaged/ misfolded proteins Accumulation of damaged proteins leads to endoplasmic
reticulum stress and apoptosis.
Chemo / radiation sensitivity IκB, P-glycoprotein, topoisomerase IIα, DNA damage NFκB is induced in response to DNA damage; normal pro-
repair enzyme downregulation teasome function is required for correct folding of P-GP;
downregulation of topoisomerase IIα may reduce sensitivity
to doxorubicin.
NFκB, Nuclear factor κB.
Adapted from Adams J: The development of proteasome inhibitors as anticancer drugs, Cancer Cell 5:417–421, 2004; Rajkumar SV, Richardson PG, Hideshima T, et al: Proteasome inhibition as a novel
therapeutic target in human cancer, J Clin Oncol 23:630–639, 2005; Voorhees PM, Dees EC, O’Neil B, et al: The proteasome as a target for cancer therapy, Clin Cancer Res 9:6316–6325, 2003.