Senolytics: charting a new course or enhancing existing anti-tumor therapies?

Abstract

Cell senescence is a natural response within our organisms. Initially, it was considered an effective anti-tumor mechanism. However, it is now believed that while cell senescence initially acts as a robust barrier against tumor initiation, the subsequent accumulation of senescent cells can paradoxically promote cancer recurrence and cause damage to neighboring tissues. This intricate balance between cell proliferation and senescence plays a pivotal role in maintaining tissue homeostasis. Moreover, senescence cells secrete many bioactive molecules collectively termed the senescence-associated secretory phenotype (SASP), which can induce chronic inflammation, alter tissue architecture, and promote tumorigenesis through paracrine signaling. Among the myriads of compounds, senotherapeutic drugs have emerged as exceptionally promising candidates in anticancer treatment. Their ability to selectively target senescent cells while sparing healthy tissues represents a paradigm shift in therapeutic intervention, offering new avenues for personalized oncology medicine. Senolytics have introduced new therapeutic possibilities by enabling the targeted removal of senescent cells. As standalone agents, they can clear tumor cells in a senescent state and, when combined with chemo- or radiotherapy, eliminate residual senescent cancer cells after treatment. This dual approach allows for the intentional use of lower-dose therapies or the removal of unintended senescent cells post-treatment. Additionally, by targeting non-cancerous senescent cells, senolytics may help reduce tumor formation risk, limit recurrence, and slow disease progression. This article examines the mechanisms of cellular senescence, its role in cancer treatment, and the importance of senotherapy, with particular attention to the therapeutic potential of senolytic drugs.

Keywords: Cancer; Cell senescence; One-Two Punch therapy; SASP; Senotherapy.

Fig. 1

Presentation of the mechanisms of senescence induction by chemotherapy. The five main groups of chemotherapeutic drugs capable of inducing senescence are Topoisomerase inhibitors, Alkylating agents, and Platinum-based compounds, Aurora Kinase inhibitors and CDK4/6 inhibitors. Topoisomerase inhibitors such as Doxorubicin, etoposide, and camptothecin can induce senescence by activating the BMP-4 Smad pathway and activating p53, p21^Cip1, and p16^INK4. Alkylating agents such as busulfan and temozolomide can induce senescence by activating the Erk-p38MAPK pathway. Platinum-based compounds such as cisplatin, carboplatin, and oxaliplatin can induce senescence by activating p53/p21 and p16. Aurora kinase inhibitors, such as Aki603 and MLN8054, can induce senescence by inhibiting Aurora-A and Aurora-B kinases, which results in the accumulation of ROS and activation of p21. CDK4/6 inhibitors such as palbociclib and abemaciclib can induce senescence by inhibiting CDK4, CDK6, FOXM1, Notch pathway and degradation of MDM2 gene

Fig. 2

Presentation of the mechanisms of senescence induction by radiotherapy. Used in radiotherapy, ionizing radiation can induce senescence by causing DNA damage, activating the p53/p21 pathway, and inducing the expression of p16

Fig. 3

Presentation of the main stages of One-Two Punch therapy