Clearance of Senescent Cells Reverses the Peripheral Neuropathy Caused by Chemotherapy

A primary goal of chemotherapy is to force cancerous cells into programmed cell death or cellular senescence. Cellular senescence is a state of growth arrest that should normally be triggered by exactly the sort of damage and dysfunction exhibited by cancer cells, but cancer is characterized by a mutation-induced ability to bypass those restrictions. Chemotherapy remains the primary approach to cancer therapy, but chemotherapeutic agents are still at best only marginally discriminating. Treating cancer with chemotherapy has always been a fine balance between harming the cancer and harming the patient. Even in the best of outcomes, it is well established that chemotherapy causes lasting damage. There are many unpleasant, lingering side-effects, and in fact chemotherapy lowers remaining life expectancy significantly. It is about as bad as a smoking habit when it comes to its effects on later mortality.

With the growing understanding of the role of senescent cells in aging, it has become clear that much of the long-term harm that results from chemotherapy results from the greatly increased burden of senescent cells that it produces. This is obviously a better outcome than dying from cancer, but it is nonetheless a problem that should be addressed. Senescent cells secrete a potent mix of inflammatory signals known as the senescence-associated secretory phenotype. This is highly disruptive to tissue function when sustained over the long term, even given a comparatively small number of senescent cells in comparison to normal cells in a tissue. Cellular senescence directly contributes to near all of the common, ultimately fatal age-related conditions.

Fortunately, the research community is developing a variety of senolytic therapies: drugs, gene therapies, immunotherapies and others, all capable of selectively destroying senescent cells. These have proven able to reverse many aspects of aging and the progression of numerous age-related diseases in animal models, and are presently undergoing human trials. It seems clear that the first senolytic therapies should be capable of reversing many of the long-term consequences of chemotherapy as well, a point well illustrated by today's open access paper.

Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice

Chemotherapy-induced peripheral neuropathy, a common dose-limiting toxicity of many chemotherapy regimens, limits the potentially curative effects of systemic chemotherapy. Particularly, platinum-based chemotherapeutics, such as cisplatin, are known to cause systemic neuronal toxicity. Clinically, cisplatin-induced peripheral neuropathy (CIPN) presents as burning, shooting or electric-shock-like pain affecting the feet and hands, for which no effective treatments or preventive measures are available.

An important senescence phenotype, termed therapy-induced senescence (TIS), can be induced by DNA damage-based chemotherapeutics. The genotoxic stress caused by these agents induces senescence during cancer treatment and has been shown to promote the adverse effects of chemotherapy. Cellular senescence, a conserved response to stress, results in a stable cell cycle arrest while maintaining cell viability and metabolic activity. The distinct metabolic and signaling features of senescent cells include a senescence-associated secretory phenotype (SASP). The expression of SASP includes the secretion of numerous molecules, including growth factors, proteases, cytokines, chemokines, and extracellular matrix components, which mediate the paracrine activities of senescent cells. Despite the relatively low proportion of senescent cells in tissues, the SASP allows these cells to generate durable local and systemic deleterious effects in most tissues, which contribute to the pathogenesis of a variety of diseases including chemotherapy toxicity.

We hypothesized that senescence and the SASP might also play a role in CIPN following neuronal DNA damage, and the depletion of senescent cells may be an effective treatment of peripheral neuropathy induced by cisplatin. We showed that cisplatin induces peripheral neuropathy, as confirmed by mechanical and thermal pain assessment, and was associated with the accumulation of senescent-like neuronal cells in the dorsal root ganglia (DRG) using immunostaining and qPCR for senescence biomarkers. Furthermore, we provided genetic and pharmacologic evidence that selective clearance of senescent-like DRG neurons alleviates CIPN.

To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological senolytic agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir to selectively kill senescent cells. We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following chemotherapeutic cancer treatment might be an effective therapy for the debilitating side effect of CIPN.