Synthetic lethal therapies for cancer: what's next after PARP inhibitors?

The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field

Age-associated deficiency in activation-induced up-regulation of telomerase activity in CD4(+) T cells

For lymphocytes, the ability to undergo clonal expansion is crucial for effective immune function. Telomerase activity compensates for telomere erosion during cell division and contributes to the capability of lymphocytes to maintain cellular proliferation. In addition, telomerase activity may have a fundamental role in cell growth and survival. To determine whether age-related immune dysfunction is associated with an abnormality in telomerase activity, we investigated telomerase activity in T cell populations from young adult and aged mice. Our data show that the ability of T cells from aged mice to up-regulate telomerase activity after activation was significantly diminished. This age-related deficiency in telomerase induction is restricted to CD4(+) T cells, as CD8(+) T cells retain the capability to up-regulate telomerase activity. These findings reinforce the notion that age-related immune dysfunction results mainly from impairment of helper T cells, and may have important implications for designing novel means to improve immune responses in aged individuals by enhancing CD8(+) T cell functions, which are crucial in both viral and tumour immunity

Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells

ARREST Of cell division is a prerequisite for cells to enter a program of terminal differentiation. Mitogenesis and cytostasis of neuronal cell precursors can be induced by the same or by different growth or trophic factors(1-9). Response of PC12 cells to nerve growth factor (NGF) involves a proliferative phase that is followed by growth arrest and differentiation. Here we present evidence that the cytostatic effect of NGF is mediated by nitric oxide (NO), a second messenger molecule with both para- and autocrine properties ties that can diffuse freely and act within a restricted volume(10-14). We show that NGF induces different forms of nitric oxide synthase (NOS) in neuronal cells, that nitric oxide (NO) acts as a cytostatic agent in these cells, that inhibition of NOS leads to reversal of NGF-induced cytostasis and thereby prevents full differentiation, and that capacity of a mutant cell line to differentiate can be rescued by exogenous NO, We suggest that induction of NOS is an important step in the commitment of neuronal precursors and that NOS serves as a growth arrest gene, initiating the switch to cytostasis during differentiation