Drug-induced senescence program may be activated both in normal and cancer cells as a consequence of chemotherapeutic treatment, leading to some adverse side effects such as senescence-associated secretory phenotype (SASP), secondary senescence, and cancer promotion. Targeted elimination of senescent cells can be achieved by drugs with senolytic activity (senolytics), for example, the plant-derived natural compound quercetin, especially when co-treated with kinase inhibitor dasatinib. In the present study, three quercetin derivatives were synthesized and tested for improved senolytic action against etoposide-induced senescent human normal mammary epithelial cells and triple-negative breast cancer cells in vitro. Transformation of catechol moiety into diphenylmethylene ketal and addition of three acetyl groups to the quercetin molecule (QD3 derivative) promoted the clearance of senescent cancer cells as judged by increased apoptosis compared to etoposide-treated cells. A QD3-mediated senolytic effect was accompanied by decreased SA-beta galactosidase activity and the levels of p27, IL-1β, IL-8, and HSP70 in cancer cells. Similar effects were not observed in senescent normal cells. In conclusion, a novel senolytic agent QD3 was described as acting against etoposide-induced senescent breast cancer cells in vitro. Thus, a new one-two punch anti-cancer strategy based on combined action of a pro-senescence anti-cancer drug and a senolytic agent is proposed.

The progressive accumulation of apoptosis-resistant and secretory active senescent cells (SCs) in animal and human aged tissues may limit lifespan and healthspan and lead to age-related diseases such as cancer, neurodegenerative disorders, and metabolic syndrome. Thus, SCs are suggested targets in anti-aging therapy. In the last two decades, a number of nanomaterials have gained much attention as innovative tools in theranostic applications due to their unique properties improving target visualization, drug and gene delivery, controlled drug release, effective diagnosis, and successful therapy. Although the healthcare industry has focused on a plethora of applications of nanomaterials, it remains elusive how nanomaterials may modulate cellular senescence, a hallmark of aging. In this review paper, we consider novel nanotechnology-based strategies for healthspan promotion and the prevention of age-related dysfunctions that are based on the delivery of therapeutic compounds capable to preferentially killing SCs (nano-senolytics) and/or modulating a proinflammatory secretome (nano-senomorphics/nano-senostatics). Recent examples of SC-targeted nanomaterials and the mechanisms underlying different aspects of the nanomaterial-mediated senolysis are presented and discussed.

5-Azacytidine (5-azaC), a methyltransferase inhibitor and anticancer drug, can promote several cellular stress responses such as apoptosis, autophagy, and senescence. The action of 5-azaC is complex and can be modulated by dose, time of treatment, and co-administration with oxidants. Insulinoma is a rare pancreatic neuroendocrine tumor with limited chemotherapeutic options. In the present study, two cellular models of insulinoma were considered, namely NIT-1 and β-TC-6 mouse cells, to evaluate the effects of 5-azaC post-treatment during hydrogen peroxide-induced oxidative stress. 5-azaC attenuated the development of oxidant-induced senescent phenotype in both cell lines. No pro-apoptotic action of 5-azaC was observed in cells treated with the oxidant. On the contrary, 5-azaC stimulated an autophagic response, as demonstrated by the increase in phosphorylated eIF2α and elevated pools of autophagic marker LC3B in oxidant-treated β-TC-6 cells. Notably, autophagy resulted in increased necrotic cell death in β-TC-6 cells with higher levels of nitric oxide compared to less affected NIT-1 cells. In addition, 5-azaC increased levels of RNA methyltransferase Trdmt1, but lowered 5-mC and m⁶A levels, suggesting Trdmt1 inhibition. We postulate that the 5-azaC anticancer action may be potentiated during oxidative stress conditions that can be used to sensitize cancer cells, at least insulinoma cells, with limited drug responsiveness.

More recently, we have proposed a safe non-vector approach to modifying the biochemical profiles of the microalga Planktochlorella nurekis and obtained twelve clones with improved content of lipids and selected pigments and B vitamins and antioxidant activity compared to unaffected cells. In the present study, the biological activity of water and ethanolic extracts of modified clones is investigated in the context of their applications in the cosmetic industry and regenerative medicine. Extract-mediated effects on cell cycle progression, proliferation, migration, mitogenic response, apoptosis induction, and oxidative and nitrosative stress promotion were analyzed in normal human fibroblasts and keratinocytes in vitro. Microalgal extracts did not promote cell proliferation and were relatively non-cytotoxic when short-term treatment was considered. Long-term stimulation with selected microalgal extracts attenuated the development of oxidative stress-induced senescence in skin cells that, at least in part, was correlated with nitric oxide signaling and increased niacin and biotin levels compared to an unmodified microalgal clone. We postulate that selected microalgal extracts of Planktochlorella nurekis can be considered to be used in skin anti-aging therapy.

Endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction are interconnected processes involved in the pathogenesis of diabetes mellitus (DM). In the present study, we demonstrate a distinct unfolded protein response (UPR) signaling pathways in two mammalian models of DM: β-TC-6 cell line and streptozotocin-induced type 1 diabetes model in rats. However, a feature common to both systems was the upregulation of the GRP78 protein. Moreover, in vivo studies showed the disruption of the antioxidant system and an escalation of mitophagy against the background of a depletion of the level of ATP in pancreatic cells. In conclusion, we suggest that glucotoxic conditions induced GRP78 upregulation, and next cause depletion of the antioxidant pool and disruption of the functioning of antioxidant defense enzymes and in consequence promote mitophagy in pancreatic cells. Therefore, GRP78 may be considered as a potential therapeutic factor in patients with diabetes.