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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 875

Mechanisms of Anticancer Activity of Histone tumor cell-selective, proapoptotic gene expression signature contain-
ing effectors of the intrinsic apoptotic pathway that conferred tumor
Deacetylase Inhibitors cell-selective apoptosis mediated by vorinostat and romidepsin. It is
not clear why matched tumor and normal cells selectively regulate a
Treatment with HDIs modulates expression of 2%–10% of a selec- subset of genes that confer tumor cell-selective, HDI-mediated
tive, but variable, subset of genes in various cell types with as many apoptosis. It is tempting to speculate that the cancer epigenome is
genes upregulated as are downregulated. Normal cells are more altered in such a way as to predispose to altered expression of apop-
resistant than cancer cells to the effects of HDIs. HDI-induced cell totic genes in response to the transformation process, but definitive
cycle arrest and apoptosis is usually correlated with upregulation of mechanistic evidence remains to be obtained.
p21, p27, and p16, and attenuation of cyclin A and D levels, leading
to decreased activity of CDK4 and CDK2. Induction of GADD45α
and -β and upregulation of TGF-β, which inhibits c-Myc, may also Classes of Histone Deacetylase Inhibitors
contribute to the cell cycle arrest in G1 or G2. Promoter regions of
p21 and the telomerase catalytic unit telomerase mutation in the Several structurally diverse classes of naturally occurring and synthetic
reverse transcriptase (TERT) have been shown to contain SP1 sites compounds have been investigated for their ability to inhibit HDAC
that bind HDAC-recruiting transcription complexes. HDIs also activity (Table 57.6). These include short-chain fatty acids (e.g.,
activate the mitochondrial apoptotic pathway by transcriptional valproic acid [VPA]), hydroxamic acid derivatives (e.g., vorinostat,
activation of apoptotic proteins such as TBP-2, Bad, Bim, Bid, BAK, panobinostat), synthetic benzamides (e.g., entinostat), and cyclic
Bax, and caspases 3 and 9, and repression of antiapoptotic proteins tetrapeptides (e.g., romidepsin). All of these have undergone clinical
such as thioredoxin, bcl-2, XIAP, and Mcl-1. HDIs have also been evaluation.
shown to upregulate Fas and the Apo-2L/TRAIL receptors DR4 and
DR5, downregulate c-FLIP, and enhance Apo-2L/TRAIL-induced Short-Chain Fatty Acid Histone Deacetylase Inhibitors
DISC and apoptosis. Sodium butyrate, a well-studied member of this class of compounds,
Treatment of leukemias with HDI alone or in combination with induces in vitro growth arrest and differentiation of human leukemia
other agents such as all-trans retinoic acid has been shown to over- cells at millimolar concentrations. Its clinical development has been
come the inhibition of differentiation caused by chimeric fusion hampered by its short half-life and difficulty in achieving millimolar
oncoproteins such as PML-RARα, PLZF-RARα, or AML-ETO. levels in vivo. Phenylbutyrate, another derivative of butyric acid, is
HDIs have also been shown to induce the expression of gelsolin, an able to induce in vitro growth arrest and differentiation of leukemia
actin-binding protein involved in morphologic and cytostructural cells at clinically achievable submillimolar concentrations. Impor-
changes associated with differentiation. Several HDIs have been tantly, at these levels, phenylbutyrate is able to synergize with retinoids
shown to induce acetylation of HSP90 and inhibit its chaperone in inducing cell cycle arrest, differentiation, and apoptosis of myeloid
association with important prosurvival client proteins such as AKT leukemia cells, and with ara-C in myeloid leukemias. VPA, a well-
and c-Raf. This directs these client proteins to polyubiquitylation and tolerated antiepileptic, was shown to be as effective as an HDI at
proteasomal degradation, thus contributing to the lowering of the levels ranging between 0.5 and 2.5 mM.
threshold for apoptosis in cancer cells. Inhibition of HDAC6 results Two phase I trials have examined the therapeutic effects of phen-
in marked accumulation of ubiquitinated proteins (inhibition of the ylbutyrate in patients with AML and MDS. No responses were noted
aggresome), via acetylation of α-tubulin, which in turn results in in either study, with neurotoxicity being the dose-limiting toxicity.
increased cellular stress and cytotoxicity. Several studies have used VPA as monotherapy or in combination
HDIs may also act by exerting antiangiogenic and immune modu- with other agents in hematologic malignancies. As monotherapy in
latory effects via downregulation of HIF-1α and epidermal growth MDS, response rates have been as high as 16% using the IWG cri-
factor. HDIs also affect cancer cell migration, invasion, and metastasis teria. Neurotoxicity has been the major side effect. Other side effects
by altering expression of extracellular matrix proteins and metastasis of VPA include thrombocytopenia, weight gain, asthenia, and rarely
genes in favor of reduced cell invasion. hepatic failure and pancreatitis. Given the low response rate, emphasis
Two reports have provided potential insights into biomarkers for has shifted to newer HDIs.
response to HDIs. The first demonstrated that enhanced JAK/STAT
signaling negatively affected HDI-induced death of CTCL cells, and Vorinostat and Other Hydroxamic Acid Derivative Histone
constitutive accumulation of STAT1 in the nucleus and high levels Deacetylase Inhibitors
of phosphorylated STAT3 correlated with a lack of response to Members of this class are some of the most potent HDIs. They
vorinostat in clinical trials. The second approach incorporated a contain a functional group that interacts with the critical zinc atom
sophisticated loss-of-function genetic screen that identified human at the base of the catalytic pocket of the class I and II HDACs. These
RAD23 homolog B (HR23B) as important for HDI-induced apop- HDIs also possess a hydrophobic cap and an aliphatic side chain that
tosis. Subsequent studies showed a correlation between HR23B interacts with the edge and fits into the hydrophobic catalytic pocket,
expression and clinical response to vorinostat, and the interaction respectively, of the HDACs. Members of this class inhibit both class
between HSP90 and HDAC6 was identified as being the crucial I and II HDACs. Vorinostat (SAHA, Zolinza) is a second-generation
functional effector mechanism delineating relative sensitivity to polar–planar compound that induces in vitro growth arrest, differen-
HDI-induced apoptosis through regulated HR23B expression. tiation, or apoptosis of a variety of cancer, leukemia, and MM cells by
Whether there is any functional interplay between JAK/STAT signal- restoring function of aberrantly silenced genes, among other effects.
ing and HR23B remains uncertain. Moreover, as HR23B expression In phase I studies, vorinostat was administered IV to patients with
can regulate sensitivity to HDIs that are very weak inhibitors of solid tumors or hematologic malignancies daily × 3 or daily × 5 for
HDAC6 (e.g., apicidin, romidepsin), it is unlikely that direct effects up to 3 weeks. The maximum tolerated dose of vorinostat in patients
2
on the HDAC6/HSP90 functional interaction account for the with hematologic malignancies was 300 mg/m daily × 5 for 3 weeks;
mechanistic role of HR23B in regulating HDI-induced apoptosis. thrombocytopenia and leukopenia were the notable toxicities, but
How or why tumor cells are more sensitive to HDI-induced induced no significant responses as a single agent in refractory AML.
apoptosis compared with matched, normal cells remains an intriguing In sequential treatments in vitro, a schedule-dependent synergy was
and largely unanswered question. Previous studies indicated that seen with other agents used to treat AML, but in some instances,
tumor cells treated with HDI preferentially accumulate reactive antagonistic activity was observed. In a phase II study of vorinostat
oxygen species (ROS) compared with treated normal cells, concomi- combined with gemtuzumab ozogamicin as induction therapy for
tant with enhanced expression of the reducing molecule thioredoxin elderly AML patients, a CR rate of more than 20% was observed. In
in normal but not tumor cells. Recently, we utilized donor-matched a phase I trial of relapsed AML, vorinostat with idarubicin induced a
normal and transformed cells treated with vorinostat to identify a 17% response rate with modification of histone acetylation patterns.