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Although chemotherapy-induced senescence (CIS) can slow tumor progression by halting the cell cycle, recent studies suggest that some cancer cells may escape this state, resume proliferation, and acquire a more aggressive phenotype. This phenomenon may contribute to chemotherapy resistance in colorectal cancer, highlighting the need to identify which treatments can effectively induce senescence. We previously demonstrated that low doses of SN38 (the active form of irinotecan) and etoposide induce senescence in HCT116 colon cancer cells, accompanied by reprogramming of the Hexosamine Biosynthesis Pathway (HBP) and O -GlcNAcylation. Here, we investigated whether other chemotherapeutic agents also induce senescence in these cells and whether changes in HBP and O-GlcNAcylation are hallmark features of CIS. Our results show that doxorubicin and cisplatin induce senescence, while 5-FU and oxaliplatin do not. Senescence induced by doxorubicin and cisplatin was associated with decreased expression of GFAT (the rate-limiting enzyme of the HBP), OGT, and OGA (the enzymes driving O -GlcNAcylation cycling), along with reduced O -GlcNAcylation levels, consistent with our previous findings. This suggests that HBP reprogramming and O -GlcNAcylation changes are hallmarks of CIS. Furthermore, they highlight the differential ability of chemotherapeutic agents to induce senescence in colorectal cancer cells, which could have implications for optimizing treatment strategies and exploring therapeutic approaches to counteract CIS. • Doxorubicin and cisplatin effectively induce senescence in HCT116 colon cancer cells, whereas 5-FU and oxaliplatin do not. • Doxorubicin- and cisplatin-induced senescence is associated with decreased expression of GFAT, OGT, OGA and O -GlcNAcylation. • These metabolic changes mirror those seen in SN38- and etoposide-induced senescence, affirming their role as CIS hallmarks. [ABSTRACT FROM AUTHOR]

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence‐associated lysosomal β‐galactosidase (SA‐β‐gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose‐encapsulated nanoparticles within these cells. Here, we show that galacto‐conjugation of the BCL‐2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav‐Gal), that can be preferentially activated by SA‐β‐gal activity in a wide range of cell types. Nav‐Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav‐Gal enhances the cytotoxicity of standard senescence‐inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav‐Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto‐conjugation reduces Navitoclax‐induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced senescent cancer cells secrete several factors in their microenvironment called SASP. Accumulated evidence states that SASP is responsible for some of the harmful effects of chemotherapy such as drug resistance and the induction of cancer cell proliferation, migration, and invasion. Therefore, to develop senolytic and/or senomorphic drugs, targeting the senescent cells gains importance as a new strategy for preventing the damage that senescent cancer cells cause. In the current work, we evaluated whether Rho/Rho kinase pathway has the potential to be used as a target pathway for the development of senolytic and/or senomorphic drugs in doxorubicin-induced senescent cancer cell lines. We have determined that inhibition of Rho/Rho kinase pathway with CT04 and Y27632 reduced the secretory activity of senescent cancer cells and changed the composition of SASP. Our results indicate that ROCK 2 isoform was responsible for these observed effects on the SASP. In addition, non-senescent cancer cell proliferation and migration accelerated by senescent cells were set back to the pre-induction levels after ROCK inhibition. Moreover, contrary to the previous observations, another important finding of the current work is that senescent HeLa and A549 cells did not engulf the non-senescent HeLa, A549 cells, and non-cancer HUVEC. These results indicate that ROCK inhibitors, in particular ROCK 2 specific inhibitors, have the potential to be developed as novel senomorphic drugs. In addition, we found that all senescent cancer cells do not share the same engulfment ability, and this process should not be generalized. [Display omitted] • Inhibition of Rho/ROCK pathway reduced the secretory activity of senescent cancer cells. • ROCK 2 isoform was responsible for the decrease in SASP. • Induced-cell proliferation and migration by senescent cells reduced by ROCK inhibition. • Senescent HeLa and A549 cells did not engulf the other cells. • ROCK 2 specific inhibitors have the potential to be developed as novel senomorphic drugs. [ABSTRACT FROM AUTHOR]