Nucleoside analogs: molecular mechanisms signaling cell death

Abstract

Nucleoside analogs are structurally similar antimetabolites that have a broad range of action and are clinically active in both solid tumors and hematological malignancies. Many of these agents are incorporated into DNA by polymerases during normal DNA synthesis, an action that blocks further extension of the nascent strand and causes stalling of replication forks. The molecular mechanisms that sense stalled replication forks activate cell cycle checkpoints and DNA repair processes, which may contribute to drug resistance. When replication forks are not stabilized by these molecules or when subsequent DNA repair processes are overwhelmed, apoptosis is initiated either by these same DNA damage sensors or by alternative mechanisms. Recently, strategies aimed at targeting DNA damage checkpoints or DNA repair processes have demonstrated effectiveness in sensitizing cells to nucleoside analogs, thus offering a means to elude drug resistance. In addition to their DNA synthesisdirected actions many nucleoside analogs trigger apoptosis by unique mechanisms, such as causing epigenetic modifications or by direct activation of the apoptosome. A review of the cellular and molecular responses to clinically relevant agents provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

“…Next, and considering the genotoxic nature of our stimulus, we studied the role of ATM and ATR in the final activation of p38MAPK. Both proteins are known to be activated by 5-FU and other nucleoside analogs (Ewald et al, 2008b). These proteins are also activators of the p38MAPK signaling pathway in different conditions, including genotoxic stress (Reinhardt et al, 2007;Perfettini et al, 2008;Lafarga et al, 2009;Reinhardt et al, 2010).…”

7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action

“…Therefore, the in vivo anticancer effect of AB61 is very promising and warrants further studies. Most of the nucleosides used in cancer therapy are incorporated into DNA leading to termination of nascent DNA strand extension and DNA damage response activation (45). In this point of view, the mechanism of action of AB61 is more complex.…”

Nucleoside analogs induce proteasomal down-regulation of p21 in chronic lymphocytic leukemia cell lines

“…A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 to activate the transcription factor p53, which results in the accumulation of its target p21, inhibition of cyclin-dependent kinase 2 (Cdk2) and G1/S-phase arrest [5,14].…”

“…One mechanism is the inhibition of DNA synthesis, including replication and repair, leading to an accumulation of DNA strand breaks and activation of the p53 pathway [4,5]. This process leads to the induction of pro-apoptotic genes, release of cytochrome c, and activation of the intrinsic pathway of apoptosis.…”