Nicotinic Acid / Nicotinamide

Author: Gianpiero Pescarmona
Date: 11/07/2008


Acido Nicotinico - Laropiprant (Pelzont)
In Data 03 Luglio 2008 la Commissione Europea ha Autorizzato all'Immissione
in Commercio il Seguente Nuovo Farmaco :
- Farmaco : Pelzont (Compresse a Rilascio Modificato)
- Principio Attivo : Acido Nicotinico 1000 mg - Laropiprant 20 mg
- ATC : C10AD52
- Categoria Farmacoterapeutica : Acido Nicotinico e Derivati
- Indicazione Terapeutica : Trattamento della Dislipidemia, Particolarmente
in Pazienti con Dislipidemia Combinata Mista ( Caratterizzata da Elevati
Livelli di Colesterolo LDL e Trigliceridi e Bassi Livelli di Colesterolo HDL) e
in Pazienti con Ipercolesterolemia Primaria ( Eterozigote Familiare e Non
Deve Essere Usato in Associazione con gli Inibitori della HMG-CoS Reduttasi
(Statine) nei Pazienti per i Quali l'Effetto Ipocolesterolemizzante degli Inibitori
della HMG-CoA Reduttasi in Monoterapia e' Inadeguato. Puo' Essere Usato
come Monoterapia solo in Pazienti nei Quali gli Inibitori della HMG-CoA
Reduttasi sono da Considerarsi Inappropriati o non Tollerati. La Dieta ed Altri
Trattamenti non Farmacologici (ad es. Esercizio Fisico, Riduzione del Peso
Corporeo) Devono Proseguire Durante la Terapia con Pelzont
Scheda Tecnica

Nicotinamide Blocks Proliferation and Induces Apoptosis of Chronic Lymphocytic Leukemia Cells through Activation of the p53/miR-34a/SIRT1 Tumor Suppressor Network. 2011 Cancer Res. 2011 Jul 1;71(13):4473-4483. Epub 2011 May 12.

Because of its relatively indolent clinical course, chronic lymphocytic leukemia (CLL) offers a versatile model for testing novel therapeutic regimens and drug combinations. Nicotinamide is the main NAD precursor and a direct inhibitor of four classes of enzymes, including the sirtuins. SIRT1, the main member of the sirtuin family, inactivates p53 by deacetylating a critical lysine residue. In this study, we showed that CLL cells express high levels of functional SIRT1, which is inhibited by exogenous nicotinamide. This agent blocks proliferation and promotes apoptosis selectively in leukemic cells that express wild-type (wt) p53. Nicotinamide modulates the p53-dependent genes p21, NOXA, BAX, and Mcl-1, indicating an activation of the p53 pathway and of caspase-3. DNA-damaging chemotherapeutics, such as etoposide, activate a functional loop linking SIRT1 and p53 through the induction of miR-34a. When leukemic cells are simultaneously exposed to nicotinamide and etoposide, we observe a significant increase in miR-34a levels with a concomitant inhibition of SIRT1. Furthermore, p53 acetylation levels are higher than with either agent used alone. Overall, treatment with both nicotinamde and etoposide shows strongly synergistic effects in the induction of apoptosis. We therefore concluded that nicotinamide has the dual property of inhibiting SIRT1 through a noncompetitive enzymatic block (p53 independent) and at the same time through miR-34a induction (p53 dependent). These observations suggested the therapeutic potential of nicotinamide, a novel, safe, and inexpensive drug, to be used in addition to chemotherapy for CLL patients with wt p53. Cancer Res; 71(13); 4473-83. ©2011 AACR.

. Conclusions and perspectives
Experience obtained in patients and in vitro after culturing and manipulating CLL cells has taught us that what is clinically considered to be the most aggressive form of the leukemia is, in fact, the most fragile. CLL cells bearing markers of aggressive disease die easily in culture and appear to have major impairments in vital signaling pathways, such as the one regulated by the antigen. One possible explanation for this apparent contradiction is that CLL cells from patients with aggressive disease are more dependent on the external environment and, once plated in an artificial culture setting, die rapidly in the absence of supporting signals from other cells. This hypothesis highlights the central role of the host environment in CLL progression and suggests that targeting the host might be a valuable complementary therapeutic approach. In this context, elucidation of the distinct microenvironmental components of the network of signals sustaining the tumor takes center stage. Expanding on experience obtained with CD38 first as a marker and then as a key element in a pathogenetic network, one might suppose that other enzymes, components of the chain that dismantles nucleotides, might contribute to modifying the environment and making it favorable to the neoplastic clone. If the observations obtained using solid tumor models are confirmed in the context of leukemia, therapeutic strategies targeting this axis may prove to be effective in fighting the disease.

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