Exploiting tumor cell senescence in anticancer therapy

Abstract

Cellular senescence is a physiological process of irreversible cell-cycle arrest that contributes to various physiological and pathological processes of aging. Whereas replicative senescence is associated with telomere attrition after repeated cell division, stress-induced premature senescence occurs in response to aberrant oncogenic signaling, oxidative stress, and DNA damage which is independent of telomere dysfunction. Recent evidence indicates that cellular senescence provides a barrier to tumorigenesis and is a determinant of the outcome of cancer treatment. However, the senescence-associated secretory phenotype, which contributes to multiple facets of senescent cancer cells, may influence both cancer-inhibitory and cancer-promoting mechanisms of neighboring cells. Conventional treatments, such as chemo- and radiotherapies, preferentially induce premature senescence instead of apoptosis in the appropriate cellular context. In addition, treatment-induced premature senescence could compensate for resistance to apoptosis via alternative signaling pathways. Therefore, we believe that an intensive effort to understand cancer cell senescence could facilitate the development of novel therapeutic strategies for improving the efficacy of anticancer therapies. This review summarizes the current understanding of molecular mechanisms, functions, and clinical applications of cellular senescence for anticancer therapy. [BMB Reports 2014; 47(2): 51-59]

The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status

“…Additionally, premature senescence, an irreversible mitotic arrest not related to telomere shortening, can be also triggered by stress induced by ionizing radiation [7,8]. It has been even hypothesized that senescence-inducing mechanisms can be applicable in the future as cancer therapies by arresting the proliferation of cancer cells through senescence induction [9][10][11]. However, radiobiological data from the last several years show that radiation is able to induce response in adjacent cells and tissues not directly subjected to radiation, the phenomenon termed the radiation induced bystander effect [reviewed in [12][13][14][15][16][17][18][19].…”

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…ATP-binding cassette (ABC) efflux transporters are well characterized as key players in suboptimal drug penetration into the tumor mass. 151 LB100 treatment in cells from the HEK293 human embryonic kidney cell line overexpressing ABC efflux transporters, Pgp, MRP1, and ABCG2, did not result in significantly different IC 50 values from treatment in ovarian cancer cells. Comparatively, treatment with paclitaxel, etoposide, and mitoxantrone all demonstrated significantly elevated IC 50 values, suggesting active drug efflux.…”

“…In particular, tumor cell senescence is a major contributor to treatment resistance, particularly with radiotherapy and conventional DNA-damaging chemo-agents that preferentially affect actively dividing cells. 50,51 Essential to cell senescence is proper functioning of PP2A during the G2 phase, during which Ras signaling is modulated to achieve stable quiescence. 28,52 Inhibition of PP2A leads to hyperactivation of Ras signaling and stabilization of c-Myc during G2, which drives cells into mitosis through accumulation of cyclin E: Cdk1 complexes.…”

Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells

“…Recently, senescence was shown to bar the initiation and development of cancer (Rodier and Campisi, 2011). Accumulating data indicate that certain therapeutic compounds or radiotherapies can induce senescence; this effect has been called therapy-induced senescence (TIS) (Suzuki and Boothman, 2008;Ewald et al, 2010;Lee and Lee, 2014). Since much lower total doses of drugs or radiation are required to induce senescence compared with cancer cell death, TIS-based strategies may trigger fewer toxicity-related side effects while stimulating tumor-specific immune activity (Kang et al, 2011;Sagiv and Krizhanovsky, 2013).…”