No abstract

Therapy-induced cellular senescence (TCS), characterized by prolonged cell cycle arrest, is an in vivo response of human cancers to chemotherapy and radiation. Unfortunately, TCS is reversible for a subset of senescent cells, leading to cellular reproliferation and ultimately tumor progression. This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer. We report the findings of a clinicopathological study in patients with locally advanced non-small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome. In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape, we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry. We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS. These polyploid senescent cells represent important transition states through which escape preferentially occurs. The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin-dependent kinase inhibitor family during TCS. Altogether, these studies underscore the importance of TCS in cancer therapeutics.The primary objective of anticancer therapy is the eradication of cancer cells by inducing cell death via apoptosis, autophagy and mitotic catastrophe. Complete eradication of most solid tumors such as non-small cell lung cancer (NSCLC) is rarely achieved using conventional treatment because of various biological and physiological limitations. These factors include the high frequency of p53 mutations, aberrant expression of antiapoptotic proteins such as Bcl-2 and survivin and various resistance mechanisms which impair tumor responses to cancer treatment. 1-3 Additionally, normal organ tolerance, drug bioavailability and tissue penetration further limit the efficacy of conventional chemotherapy and radiation in clinical settings.Telomere-independent therapy-induced cellular senescence (TCS), also known as stressed-induced premature senescence and accelerated cellular senescence, is increasingly recognized to be an important concept in cancer biology. The characteristic prolonged state of cell cycle arrest which defines senescence is elicited by sublethal doses of chemotherapy and ionizing radiation. 4,5 Over the past decade, TCS has been clearly demonstrated in a variety of cancer tissue culture models following abbreviated courses of antineoplastic drugs at subtumoricidal concentrations. 6 These studies consistently show that senescence response can be invoked by a wide spectrum of agents, which suggests that shared downstream pathways may be triggered by various cellular damage and stress signals. A particularly surprising finding is that despite expected dependency on key players of the cell damage and replicative

Daily injection of microgram amounts of melatonin in rats decreased the incidence of estrus and reduced ovarian weight. Circulating melatonin was selectively taken up and retained by the ovary and pineal gland; this effect was reduced by exposure of rats to constant light. A single injection of melatonin lowered the incidence of estrus among rats exposed to constant light.