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Pippione et al. Steroidogenic enzymes in prostate cancer

activity toward HSD17Bs of other species, especially the distribution of SRD5A1-3 in different human
rodents [73,75,77] . Moreover, as AKR1C3, predominantly tissues is tabulated in the review of Azzouni et al. [88] ,
expressed in the prostate, performs the same which extensively examines the basic biology of the
biochemical conversions of HSD17B3, the in vivo SRD5A isoenzyme family. The different expression
HSD17B3 inhibition alone is not sufficient to completely levels of SRD5A isoenzymes may confer response
abolish T levels in plasma. Additionally, the complexity or resistance to 5a-reductase inhibitors and thus may
and versatility of the steroidogenic pathways could have importance in PCa prevention. The mechanisms
bypass HSD17B3 inhibition in vivo, rendering these underlying androgen regulation of expression of the
inhibitors not sufficiently efficacious in blocking tumour three different SRD5A isoenzymes in human prostate
progression when tested alone. cells has been investigated by Li et al. [89] . The authors
found that androgens regulate the mRNA levels of
SRD5A SRD5A isoenzymes in a cell type-specific manner,
Steroid 5α-reductases (SRD5A) are membrane- with regulation occuring at the transcriptional level
associated (microsomal) enzymes thatcatalyse the and dependent on the AR. In addition, AR seems be
5α-reduction of 3-oxo (3-keto), Δ4,5 C19/C21 steroids. recruited to a negative androgen response element
The reaction involves a stereospecific, irreversible (nARE) at the promoter of SRD5A3 in vivo and directly
breakage of the double bond between carbons 4 and binds to the nARE in vitro.
5 with the aid of cofactor NADPH and the insertion of a
hydride anion to the α face at carbon C-5 and a proton Due to the unstable nature of these enzymes during
to the β face at position C-4. Examples of substrates purification, the crystal structures of both SRD5A1
are T, progesterone, AD, epitestosterone, cortisol, and SRD5A2 are still unresolved. Despite this, a large
aldosterone and deoxycorticosterone. number of molecules has been developed as SRD5A
inhibitors over the past 40 years. Finasteride (38, Figure
Three isoenzymes of SRD5A, which are encoded by 11) and dutasteride (39) are the only two clinically
different genes (SRD5A1, SRD5A2, and SRD5A3), used drugs, having been approved by the FDA for the
have been identified. All are involved in the conversion treatment of BPH in 1992 and 2002, respectively [90,91] .
of T into DHT in the canonical pathway. In addition, Finasteride is a potent inhibitor of SRD5A2 with only
SRD5A enzymes are also involved in the reduction weak in vitro activity versus SRD5A1 having IC 50
of AD and progesterone or 17α-hydroxyprogesterone value of 9.4 and 410 nmol/L on the isolated enzyme,
respectively to 5α-androstanedione and pregnan-3,20- respectively [92,93] . Dutasteride on the other hand, is a
dione or pregnan-3α,17α-dihydroxy-20-one. Therefore, dual inhibitor of both SRD5A1 and SRD5A2 isozymes,
these reductases appear to be key enzymes for the with IC 50 of 2.4 and 0.5 nmol/L respectively [94] . Both
activation of both 5α-dione and backdoor pathways drugs are time-dependent competitive inhibitors and
[Figure 2]. belong to the 4-azasteroids class of steroidal SRD5A
inhibitors.
Even though these three isozymes are intrinsic
membrane-bound proteins that catalyse the same A detailed review of each category of inhibitors
reaction, they only share a limited degree of synthesised was published in 2010 [93] , and aids
homology in protein sequence and possess distinctive understanding of the structural features required
biochemical properties. SRD5A1 is expressed in low for SRD5A inhibitory activity. The review discussed
levels in the prostate, and is relatively insensitive the need for more potent and less toxic inhibitors of
to finasteride, a 4-azasteroid enzyme inhibitor (38, SRD5A and suggested the use of molecules outside
Figure 11). SRD5A2 is expressed in high levels in the the steroidal template, as they can decrease the
prostate and in many other androgen-sensitive tissues potential interaction with an additional enzyme or
and is sensitive to finasteride. Instead, it remains receptor of the steroidal endocrine system. Since 2010,
controversial whether SRD5A3 enzyme activity is only a few molecules have emerged as nonsteroidal
inhibited by finasteride or dutasteride, the latter a SRD5A inhibitors [95] . In 2011, a hybrid molecule
4-azasteroid derivative effective at inhibiting both (40) was derived by merging structural features of
SRD5A1 and SRD5A2 [87] . finasteride and epristeride (41) as an inhibitor of
SRD5A2. As epristeride behaves as an uncompetitive
The inter- and intra-individual variability, the type and inhibitor [93,95,96] , a hybrid compound from these two
stages of progression of PCa and the methods used molecules could have propensity for exploiting both
could explain the differences in the expression of the mechanisms. However, the relative potency of 40
3 isoenzymes observed in numerous reports [Table 2]. was only 0.49 (compared with finasteride), and the
A summary of many studies that have discussed authors concluded, from observing docking poses of

344 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017