MED
DOI: 10.1002/cmdc.201200318
Carprofen Analogues as Sirtuin Inhibitors: Enzyme and Cellular Studies
Paolo Mellini,[a] Vincenzo Carafa,[b] Barbara Di Rienzo,[a] Dante Rotili,[a] Daniela De Vita,[a] Roberto Cirilli,[c]
Bruno Gallinella,[c] Donatella Paola Provvisiero,[b] Salvatore Di Maro,[d] Ettore Novellino,[d] Lucia Altucci,*[b, e] and
Antonello Mai*[a]
Among the histone deacetylase (HDAC) family, class III HDACs,
also named sirtuins (SIRT1–7),[1] are characterized by a con-
served 270-amino-acid catalytic core domain, and catalyze the
removal of an acetyl moiety from the e-amino group of lysine
residues through a NAD+-dependent deacetylation mecha-
nism.[2] In addition to histones (H1, H3, and H4), SIRTs can de-
acetylate a variety of nonhistone substrates (e.g., FoxO, NF-kB,
p53, p73, p300, a-tubulin, etc.), thus playing critical roles in dif-
ferent biological processes including control of gene expres-
sion, metabolism, and aging.[3,4] In particular, deregulation of
SIRT1 is involved in many human processes or diseases, such
as obesity, inflammation,[5,6] muscle differentiation,[7] and neu-
rodegeneration.[8]
Despite SIRT2 having been initially considered less involved
than SIRT1 in cancer development due to its mainly cytosolic
localization and its ability to deacetylate a-tubulin, its role in
the pathogenesis and development of cancer has been recent-
ly suggested.[13,14] Thus, dual inhibition of SIRT1 and SIRT2 is
now deemed necessary to obtain efficient antitumor effect.[15]
To date, a few SIRT1/2 inhibitors have been validated in
cancer. Sirtinol was reported to induce senescence-like growth
arrest in human breast cancer (MCF-7) cells and lung cancer
In cancer, the role of SIRT1 is highly debated. Indeed, on
one hand, SIRT1 was found to be upregulated in many malig-
nancies, such as human prostate cancer, acute myeloid leuke-
mia, nonmelanoma skin cancer, primary colon cancer, and
breast cancer.[9] In addition, SIRT1 might promote tumorigene-
sis as a result of the negative regulation of the tumor suppres-
sor proteins p53, hypermethylated in cancer 1 (HIC1), and de-
leted in breast cancer 1 (DBC1).[9] On the other hand, SIRT1 ex-
pression was found to be reduced in glioblastoma, bladder
carcinoma, prostate carcinoma, and ovarian cancer, when com-
pared to the corresponding normal tissues,[10] and overexpres-
sion of SIRT1 in APCmin/+ mice showed a protective role in
colon cancer.[11] Thus, depending on the experimental model
and the tumor type under study, it seems that SIRT1 might be
involved in tumor promoter or tumor suppressor functions.[12]
[a] Dr. P. Mellini,+ Dr. B. Di Rienzo, Dr. D. Rotili, Dr. D. De Vita, Prof. A. Mai
Istituto Pasteur—Fondazione Cenci Bolognetti
(H1299) cells,[16,17] and very recently, it has been shown to
modulate androgen-, estrogen-, and insulin-like growth factor-
1-mediated pathways in LNCaP cells, with effects not due
solely to sirtuin inhibition.[18] Cambinol induces apoptosis in
BCL6-expressing Burkitt lymphoma cells,[19] salermide shows
tumor-specific apoptosis in a wide range of human cancer cell
lines,[20] tenovins decrease tumor growth in vivo as single
agents at low micromolar concentrations,[21] and MC2141 dis-
plays high antiproliferative activity against Raji, DLD1, and
HeLa cells.[22] In contrast, SIRT1-selective inhibitor selisistat (EX-
527, SEN0014196)[23] efficiently increases p53 acetylation in
cells without reported effects on cell growth, viability, or p53-
controlled gene expression,[24] and it has entered phase II clini-
cal trials for the treatment of Huntington’s disease.[25]
Dipartimento di Chimica e Tecnologie del Farmaco
Sapienza Universitꢀ di Roma, P.le A. Moro 5, 00185 Roma (Italy)
[b] Dr. V. Carafa,+ Dr. D. P. Provvisiero, Prof. L. Altucci
Dipartimento di Patologia Generale
Seconda Universitꢀ degli Studi di Napoli
vico L. De Crecchio 7, 80138 Napoli (Italy)
[c] Dr. R. Cirilli, Dr. B. Gallinella
Dipartimento del Farmaco, Istituto Superiore di Sanitꢀ
Viale Regina Elena 299, 00161 Rome (Italy)
[d] Dr. S. Di Maro, Prof. E. Novellino
Dipartimento di Chimica Farmaceutica e Tossicologica
Universitꢀ di Napoli “Federico II”
Via D. Montesano, 49, 80131 Napoli (Italy)
[e] Prof. L. Altucci
Institute of Genetics and Biophysics (IGB)–CNR
Via P. Castellino, 80100, Napoli (Italy)
Nonsteroidal anti-inflammatory drug (NSAID) carprofen was
shown to activate the p38 mitogen-activated protein kinase
(MAPK) pathway leading to an increased level of p75NTR protein
and induction of apoptosis in prostate (PC-3 and DU-145) and
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
ChemMedChem 0000, 00, 1 – 4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!