Senolytics... Supporting the Outcomes of Chemotherapy
Cancer is a leading cause of death worldwide, and chemotherapy remains one of the primary treatment modalities for many types of cancer. Despite its effectiveness in killing cancer cells, chemotherapy can also induce cellular senescence in healthy tissues, leading to a range of adverse side effects and potentially contributing to cancer recurrence and metastasis. Senescent cells, which accumulate in tissues with age and in response to various stressors, including chemotherapy, can create a pro-inflammatory and immunosuppressive microenvironment that promotes cancer growth and reduces the efficacy of chemotherapy.
Senescent cells are cells that have stopped dividing but remain metabolically active. They can accumulate in tissues with age or in response to various stressors, such as DNA damage, oxidative stress, or chemotherapy. While cellular senescence is a normal biological process that helps prevent the proliferation of damaged or potentially cancerous cells, the excessive accumulation of senescent cells can have detrimental effects on health, particularly in the context of aging and cancer treatment.
Table of Contents:
Impact on Aging
Chronic inflammation: Senescent cells secrete a variety of pro-inflammatory factors, collectively known as the senescence-associated secretory phenotype (SASP). These factors can contribute to chronic low-grade inflammation, a hallmark of aging that is associated with various age-related diseases, such as cardiovascular disease, neurodegenerative disorders, and cancer.
Tissue dysfunction: The accumulation of senescent cells can impair tissue function by disrupting the normal cellular composition and microenvironment. This can lead to reduced tissue regeneration, impaired wound healing, and decreased organ function, contributing to the age-related decline in physical and cognitive abilities.
Stem cell exhaustion: Senescent cells can negatively impact the function of stem cells, which are essential for tissue maintenance and repair. The SASP factors secreted by senescent cells can impair stem cell self-renewal and differentiation, leading to a decline in tissue regenerative capacity with age.
Impact on Cancer Treatment
Chemotherapy resistance: Senescent cells can secrete factors that promote the survival and growth of neighboring cancer cells, potentially reducing the effectiveness of chemotherapy. The SASP factors can also create a pro-tumorigenic microenvironment that supports cancer cell proliferation and invasion, leading to chemotherapy resistance.
Side effects: Chemotherapy can induce cellular senescence in healthy tissues, contributing to the development of side effects such as fatigue, muscle weakness, and cognitive impairment. The accumulation of chemotherapy-induced senescent cells can exacerbate these side effects and reduce the quality of life for cancer patients undergoing treatment.
Cancer recurrence and metastasis: Senescent cells can create an immunosuppressive microenvironment that impairs the function of immune cells, such as T cells and natural killer cells, which are crucial for targeting and eliminating cancer cells. This immunosuppressive environment can promote cancer recurrence and metastasis, even after successful initial treatment.
Accelerated aging: Cancer survivors often experience accelerated aging, characterized by the early onset of age-related diseases and functional decline. The accumulation of senescent cells induced by chemotherapy and other cancer treatments may contribute to this accelerated aging process, increasing the risk of long-term health complications.
Given the detrimental effects of senescent cells on aging and cancer treatment, targeting and eliminating these cells has become a promising therapeutic approach. Senolytics, compounds that selectively clear senescent cells, have shown potential in preclinical studies to alleviate age-related pathologies, enhance the efficacy of chemotherapy, reduce side effects, and prevent cancer recurrence and metastasis. As always, more human clinical trials are needed to validate the safety and efficacy of senolytics in the context of aging and cancer treatment.
Enhancing Chemotherapy Efficacy
Chemotherapy is a cornerstone of cancer treatment, but its effectiveness can be compromised by the presence of senescent cells in the tumor microenvironment. Senescent cells, although no longer capable of cell division, remain metabolically active and can secrete a wide array of factors, collectively known as the senescence-associated secretory phenotype (SASP). These SASP factors, which include pro-inflammatory cytokines, growth factors, and proteases, can create a supportive microenvironment for cancer cells, promoting their survival, growth, and resistance to chemotherapy.
When cancer cells are exposed to chemotherapy, some of them may stop dividing and enter a state called senescence. Although these senescent cells are not actively growing, they can still have harmful effects on the body.
Senescent cells can release certain substances, such as interleukin-6 (IL-6) and interleukin-8 (IL-8), into their surroundings. These substances can then interact with nearby cancer cells, triggering a series of events within the cancer cells that make them more resistant to chemotherapy.
For example, IL-6 and IL-8 can activate specific pathways (sequences of molecular interactions) inside the cancer cells, such as the JAK/STAT and PI3K/AKT pathways. When these pathways are activated, they can help cancer cells survive by preventing them from undergoing apoptosis, which is a type of programmed cell death that chemotherapy aims to induce. Additionally, these pathways can cause cancer cells to produce more proteins called drug efflux pumps, which can pump chemotherapy drugs out of the cells, reducing their effectiveness. Senescent cells can also stimulate a process called epithelial-to-mesenchymal transition (EMT) in cancer cells. EMT is a process where cancer cells change their characteristics, making them more capable of spreading to other parts of the body (metastasis) and more resistant to chemotherapy.
Elimination of Senescent Cells
The elimination of senescent cells using senolytics has emerged as a promising strategy to enhance the efficacy of chemotherapy. Senolytics are compounds that selectively target and eliminate senescent cells, either by inducing apoptosis or by inhibiting the pro-survival pathways that maintain their viability. By clearing senescent cells from the tumor microenvironment, senolytics can help overcome the chemotherapy resistance mediated by SASP factors and create a less supportive niche for cancer cell survival and growth.
Several preclinical studies have demonstrated the potential of senolytics to improve the efficacy of chemotherapeutic agents in various cancer types. For instance, in a study on breast cancer, the combination of the senolytic drug navitoclax (ABT-263) with the chemotherapeutic agent doxorubicin significantly reduced tumor growth and improved survival in mice compared to either treatment alone. The study found that navitoclax eliminated senescent cells induced by doxorubicin treatment, thereby reducing the SASP-mediated chemotherapy resistance and enhancing the sensitivity of cancer cells to the treatment.
Similarly, in a study on lung cancer, the senolytic combination of dasatinib and quercetin (D+Q) enhanced the efficacy of the chemotherapeutic agent cisplatin. The D+Q treatment reduced the number of senescent cells in the tumor microenvironment, decreased the expression of SASP factors, and sensitized lung cancer cells to cisplatin-induced apoptosis. These findings suggest that senolytics can help overcome chemotherapy resistance and improve treatment outcomes in lung cancer.
In ovarian cancer, senescent cells have been shown to contribute to the development of chemotherapy resistance and tumor recurrence. A preclinical study demonstrated that the senolytic drug fisetin enhanced the efficacy of the chemotherapeutic agent paclitaxel in ovarian cancer models. Fisetin treatment reduced the number of senescent cells, decreased the expression of SASP factors, and sensitized ovarian cancer cells to paclitaxel-induced cell death. These results highlight the potential of senolytics to improve chemotherapy efficacy and prevent tumor recurrence in ovarian cancer.
The promising preclinical evidence supporting the use of senolytics to enhance chemotherapy efficacy has led to the initiation of clinical trials investigating the combination of senolytics with standard chemotherapeutic agents. These trials aim to validate the safety and efficacy of senolytic interventions in cancer patients and explore the potential of senolytics to improve treatment outcomes, reduce side effects, and prevent cancer recurrence and metastasis.
Senescent cells can contribute to chemotherapy resistance and compromise the effectiveness of cancer treatment. The use of senolytics to eliminate senescent cells has shown promise in preclinical studies, improving the efficacy of chemotherapeutic agents in various cancer types, including breast, lung, and ovarian cancers. By clearing senescent cells and their associated SASP factors, senolytics may help overcome chemotherapy resistance, enhance the sensitivity of cancer cells to treatment, and ultimately improve patient outcomes. As clinical trials progress, the combination of senolytics with standard chemotherapy regimens may emerge as a novel therapeutic strategy to enhance the effectiveness of cancer treatment and improve the lives of cancer patients.
Reducing Chemotherapy-Induced Side Effects
Chemotherapy, while it can be effective in killing cancer cells, can also cause significant side effects that negatively impact the quality of life for cancer patients. These side effects can range from mild to severe and can include fatigue, muscle weakness, cognitive impairment, neuropathy, and gastrointestinal issues. One of the mechanisms contributing to these side effects is the induction of cellular senescence in healthy tissues by chemotherapeutic agents.
Chemotherapy-induced senescence occurs when the DNA damage caused by chemotherapeutic drugs triggers a permanent cell cycle arrest in normal, non-cancerous cells. These senescent cells, although no longer dividing, remain metabolically active and secrete a variety of pro-inflammatory factors, growth factors, and proteases, collectively known as the senescence-associated secretory phenotype (SASP). The accumulation of senescent cells and their associated SASP factors in healthy tissues can contribute to the development of chemotherapy-induced side effects.
For example, chemotherapy-induced senescent cells in the brain have been linked to cognitive impairment, often referred to as "chemobrain." The SASP factors secreted by these senescent cells can cause neuroinflammation, disrupt neural network function, and impair cognitive processes such as memory and attention. Similarly, the accumulation of senescent cells in skeletal muscle can contribute to muscle weakness and fatigue, as the SASP factors can promote muscle catabolism and inhibit muscle regeneration.
Senolytic agents, which selectively eliminate senescent cells, have emerged as a promising approach to alleviate chemotherapy-induced side effects. By reducing the burden of senescent cells in affected tissues, senolytics can help mitigate the detrimental effects of the SASP and improve the overall health and function of these tissues.
Preclinical studies have demonstrated the potential of senolytic agents to alleviate chemotherapy-induced side effects in animal models. For instance, in a study on mice, the senolytic combination of dasatinib and quercetin (D+Q) was shown to alleviate chemotherapy-induced fatigue and muscle weakness. Mice treated with the chemotherapeutic agent doxorubicin exhibited significant increases in senescent cells in skeletal muscle, along with reduced muscle strength and increased fatigue. However, when these mice were treated with the D+Q senolytic combination, the number of senescent cells in skeletal muscle was significantly reduced, and the mice exhibited improved muscle strength and reduced fatigue compared to those treated with doxorubicin alone.
Similarly, senolytic agents have shown promise in alleviating chemotherapy-induced cognitive impairment. In a preclinical study, the senolytic drug ABT-263 (navitoclax) was found to reduce the number of senescent cells in the brains of mice treated with the chemotherapeutic agent cisplatin. The elimination of senescent cells by ABT-263 was associated with reduced neuroinflammation and improved cognitive function in these mice, suggesting that senolytics may help prevent or reverse chemotherapy-induced cognitive deficits.
The promising preclinical evidence supporting the use of senolytics to alleviate chemotherapy-induced side effects has led to the initiation of clinical trials investigating the safety and efficacy of senolytic interventions in cancer patients undergoing chemotherapy. These trials aim to evaluate whether senolytics can reduce the burden of senescent cells in affected tissues, mitigate chemotherapy-induced side effects, and improve the overall quality of life for cancer patients.
Chemotherapy-induced cellular senescence in healthy tissues is a significant contributor to the development of side effects such as fatigue, muscle weakness, and cognitive impairment. The accumulation of senescent cells and their associated SASP factors can disrupt the normal function of affected tissues and exacerbate the negative impact of chemotherapy on patient quality of life. Senolytic agents, by selectively eliminating senescent cells, have shown promise in preclinical studies to alleviate chemotherapy-induced side effects and improve the overall health and function of affected tissues. As clinical trials progress, the use of senolytics in combination with chemotherapy may emerge as a novel therapeutic strategy to reduce the burden of side effects and improve the quality of life for cancer patients undergoing treatment.
Preventing Cancer Recurrence and Metastasis
Cancer recurrence and metastasis are major challenges in the successful treatment of cancer. Even after initial therapy, cancer cells can remain dormant in the body and later reactivate, leading to the recurrence of the primary tumor or the development of metastatic lesions in distant organs. Emerging evidence suggests that senescent cells play a crucial role in creating a pro-tumorigenic microenvironment that promotes cancer recurrence and metastasis.
Senescent cells, although no longer capable of cell division, secrete a wide array of pro-inflammatory cytokines, growth factors, and proteases, known as the senescence-associated secretory phenotype (SASP). The SASP factors can create a chronic inflammatory state in the tumor microenvironment, which can promote the survival, growth, and invasive properties of residual cancer cells. Moreover, senescent cells can induce an immunosuppressive microenvironment by secreting factors that inhibit the function of immune cells, such as T cells and natural killer cells, which are crucial for the immune system's ability to recognize and eliminate cancer cells.
The pro-tumorigenic and immunosuppressive effects of senescent cells can contribute to cancer recurrence and metastasis. For example, senescent fibroblasts in the tumor stroma have been shown to secrete factors that stimulate the proliferation and invasiveness of cancer cells, as well as promote angiogenesis, the formation of new blood vessels that support tumor growth. Additionally, senescent cells can facilitate the epithelial-to-mesenchymal transition (EMT) in cancer cells, a process that enables them to detach from the primary tumor, invade surrounding tissues, and establish metastatic lesions in distant organs.
Preclinical studies
Preclinical studies have demonstrated the potential of senolytic agents to reduce the risk of cancer recurrence and metastasis by eliminating senescent cells and modulating the tumor microenvironment. Senolytic agents selectively target and eliminate senescent cells, either by inducing apoptosis or by inhibiting the pro-survival pathways that maintain their viability. By removing senescent cells and their associated SASP factors, senolytics can help to create a less supportive microenvironment for the survival and growth of residual cancer cells.
In a groundbreaking study on mice with breast cancer, treatment with the senolytic drug navitoclax (ABT-263) after chemotherapy significantly reduced the risk of cancer recurrence and metastasis. Mice treated with the chemotherapeutic agent doxorubicin exhibited an increase in senescent cells in the primary tumor site and distant organs, along with an elevated expression of pro-tumorigenic SASP factors. However, when these mice were subsequently treated with navitoclax, the number of senescent cells was significantly reduced, and the expression of SASP factors was suppressed. Notably, the mice treated with the combination of chemotherapy and navitoclax exhibited a significantly lower incidence of cancer recurrence and metastasis compared to those treated with chemotherapy alone.
The study also revealed that navitoclax treatment reduced the recruitment of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), to the tumor site. These immunosuppressive cells can inhibit the function of anti-tumor immune cells and promote a pro-tumorigenic microenvironment. By reducing the presence of these cells, navitoclax treatment helped to restore the immune system's ability to recognize and eliminate residual cancer cells, thereby reducing the risk of cancer recurrence and metastasis.
The promising preclinical evidence supporting the use of senolytics to prevent cancer recurrence and metastasis has led to the initiation of clinical trials investigating the safety and efficacy of senolytic interventions in cancer patients. These trials aim to evaluate whether senolytics can reduce the burden of senescent cells in the tumor microenvironment, modulate the immune system's anti-tumor response, and ultimately improve long-term cancer outcomes.
Enhancing Immune-Mediated Cancer Cell Clearance
The immune system plays a critical role in the body's defense against cancer. Immune cells, such as T cells and natural killer (NK) cells, are responsible for recognizing and eliminating cancer cells. However, the presence of senescent cells in the tumor microenvironment can impair the function of these immune cells, thereby compromising the immune system's ability to control cancer growth and progression. Senolytic agents, by targeting and eliminating senescent cells, have shown promise in enhancing immune-mediated cancer cell clearance and promoting long-term cancer control.
Senescent cells can contribute to an immunosuppressive tumor microenvironment through the secretion of various factors, collectively known as the senescence-associated secretory phenotype (SASP). The SASP includes pro-inflammatory cytokines, growth factors, and chemokines that can directly inhibit the function of immune cells or recruit immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), to the tumor site. These immunosuppressive cells can further dampen the anti-tumor immune response and promote tumor growth and progression.
For example, senescent cells have been shown to secrete high levels of TGF-β, a potent immunosuppressive cytokine that can inhibit the proliferation and effector functions of T cells. Additionally, senescent cells can secrete chemokines, such as CCL2 and CXCL12, which can attract Tregs and MDSCs to the tumor site, further contributing to an immunosuppressive microenvironment. The accumulation of these immunosuppressive cells can hinder the ability of anti-tumor immune cells, such as CD8+ T cells and NK cells, to effectively recognize and eliminate cancer cells.
Senolytics alleviate the immunosuppressive effects
Senolytic agents, by selectively eliminating senescent cells and their associated SASP factors, have the potential to alleviate the immunosuppressive effects of senescent cells and enhance immune-mediated cancer cell clearance. Preclinical studies have demonstrated that the elimination of senescent cells using senolytics can improve the function of anti-tumor immune cells and promote a more robust immune response against cancer.
In a study using a mouse model of breast cancer, treatment with the senolytic drug ABT-737 (a BCL-2 family inhibitor) significantly reduced the number of senescent cells in the tumor microenvironment. The elimination of senescent cells was accompanied by a marked increase in the infiltration of CD8+ T cells and NK cells into the tumor, as well as enhanced cytotoxic activity of these immune cells against cancer cells. Moreover, the combination of ABT-737 with immune checkpoint inhibitors, such as anti-PD-1 antibodies, further potentiated the anti-tumor immune response and led to improved tumor control and survival in the mice.
Similarly, in a study using a mouse model of lung cancer, treatment with the senolytic combination of dasatinib and quercetin (D+Q) enhanced the efficacy of anti-PD-1 immunotherapy. The elimination of senescent cells by D+Q reduced the levels of immunosuppressive SASP factors, such as TGF-β and IL-6, in the tumor microenvironment. This reduction in immunosuppressive factors was associated with an increased infiltration of CD8+ T cells into the tumor and enhanced anti-tumor immune responses. Mice treated with the combination of D+Q and anti-PD-1 antibodies exhibited significantly improved tumor control and survival compared to those treated with either agent alone.
The promising preclinical evidence supporting the use of senolytics to enhance immune-mediated cancer cell clearance has led to the initiation of clinical trials investigating the combination of senolytics with immunotherapies, such as immune checkpoint inhibitors, in cancer patients. These trials aim to evaluate whether the elimination of senescent cells by senolytics can improve the efficacy of immunotherapies and promote long-term cancer control.
Senescent cells play a crucial role in creating a pro-tumorigenic and immunosuppressive microenvironment that promotes cancer recurrence and metastasis. The SASP factors secreted by senescent cells can stimulate the survival, growth, and invasive properties of residual cancer cells, as well as inhibit the function of anti-tumor immune cells. Senolytic agents, by selectively eliminating senescent cells and their associated SASP factors, have shown promise in preclinical studies to reduce the risk of cancer recurrence and metastasis. As clinical trials progress, the use of senolytics as an adjuvant therapy to conventional cancer treatments may emerge as a novel strategy to improve long-term cancer outcomes and reduce the burden of cancer recurrence and metastasis.
Recognizing the need for clinical validation, several ongoing clinical trials are currently investigating the use of senolytics in cancer patients undergoing chemotherapy. These trials are designed to comprehensively assess the impact of senolytics on various aspects of cancer treatment, including their ability to enhance chemotherapy efficacy, mitigate side effects, and improve long-term cancer outcomes.
More Studies
For instance, the SENOMAC trial (NCT04733534), a phase II clinical study, is evaluating the combination of the senolytic drug navitoclax (ABT-263) with the chemotherapeutic agent gemcitabine in patients with advanced pancreatic cancer. The primary objectives of this trial are to determine whether the addition of navitoclax to gemcitabine can improve tumor response rates, progression-free survival, and overall survival compared to gemcitabine alone. Additionally, the trial will assess the safety profile and tolerability of the combination therapy and investigate the impact of navitoclax on the immune system and the tumor microenvironment.
Similarly, the SENATOR trial (NCT04685590), a phase I/II clinical study, is exploring the use of the senolytic combination of dasatinib and quercetin (D+Q) in patients with various advanced solid tumors, such as breast, lung, and colorectal cancers. This trial aims to evaluate the safety, tolerability, and preliminary efficacy of D+Q in combination with standard chemotherapy regimens. Furthermore, the study will examine the impact of D+Q on the tumor microenvironment, immune cell function, and the abundance of senescent cells in tumor biopsies.
The results of these ongoing clinical trials, along with others in the pipeline, will provide crucial insights into the potential of senolytics as adjuvant therapies to enhance the effectiveness of chemotherapy, alleviate its adverse effects, and ultimately improve cancer treatment outcomes. However, it is important to acknowledge that the outcomes of these trials may vary depending on factors such as the specific cancer type, disease stage, and the particular senolytic agent and chemotherapeutic regimen employed.
As the field of senolytic research advances, determining the optimal timing, dosage, and combination of senolytics with chemotherapeutic agents for different cancer types will require carefully designed clinical studies. Considerations such as the pharmacokinetic and pharmacodynamic properties of the senolytic agents, potential drug-drug interactions, and patient-specific factors will need to be taken into account to optimize the benefits and minimize the risks associated with combining senolytics with chemotherapy.
Moreover, long-term follow-up studies will be crucial to assess the impact of senolytic interventions on cancer recurrence, metastasis, and overall survival. These studies will help determine whether the use of senolytics as adjuvant therapies can provide durable benefits for cancer patients and improve their long-term outcomes.
While the preclinical findings on the use of senolytics to support chemotherapy outcomes are indeed promising, more human clinical trials are necessary to validate their safety, efficacy, and clinical utility. Ongoing and future clinical trials will yield valuable insights into the potential of senolytics as adjuvant therapies in cancer treatment. As research progresses, the optimal strategies for incorporating senolytics into cancer care will be refined, potentially leading to improved treatment outcomes and quality of life for cancer patients undergoing chemotherapy.
Here are some of the natural senolytics that are currently being explored and evaluated:
Fisetin:
A flavonoid found in various fruits and vegetables, such as strawberries, apples, and cucumbers.
Has been shown to have senolytic properties in preclinical studies, selectively eliminating senescent cells and reducing inflammation.
Currently being investigated in clinical trials for its potential to enhance the efficacy of chemotherapy and reduce side effects.
Curcumin:
The main active compound found in turmeric, a spice commonly used in Indian and Middle Eastern cuisine.
Has been shown to have senolytic properties in preclinical studies, reducing the accumulation of senescent cells and inflammation.
Being investigated for its potential to enhance the efficacy of chemotherapy and reduce side effects.
Piperlongumine:
A natural compound found in the long pepper plant (Piper longum).
Has been shown to have senolytic properties in preclinical studies, selectively eliminating senescent cells and reducing inflammation.
Being investigated for its potential to enhance the efficacy of chemotherapy and reduce side effects.
Quercetin:
A flavonoid found in many fruits, vegetables, and herbs, such as onions, apples, and green tea.
Has been shown to have senolytic properties, particularly in combination with other compounds like dasatinib.
Being studied for its potential to improve the effectiveness of chemotherapy and reduce side effects.
Epigallocatechin gallate (EGCG):
A polyphenol found in green tea.
Has been shown to have senolytic properties in preclinical studies, selectively eliminating senescent cells and reducing inflammation.
Being studied for its potential to improve the effectiveness of chemotherapy and reduce side effects.
Genistein:
An isoflavone found in soybeans and other legumes.
Has been shown to have senolytic properties in preclinical studies, selectively eliminating senescent cells and reducing inflammation.
Being studied for its potential to improve the effectiveness of chemotherapy and reduce side effects.
Resveratrol:
A polyphenol found in grapes, red wine, and certain berries.
Has been shown to have senolytic properties in preclinical studies, reducing the accumulation of senescent cells and inflammation.
Being investigated for its potential to enhance the efficacy of chemotherapy and reduce side effects.
These natural senolytics are currently being explored in preclinical studies and some early-stage clinical trials. While the initial findings are promising, more research is needed to fully understand their potential benefits, optimal dosing, and long-term safety when used in combination with chemotherapy. As with any natural compound or supplement, it is essential to consult with a healthcare professional before incorporating them into a treatment plan, as they may interact with other medications or have potential side effects.
https://www.mdpi.com/2072-6694/14/3/605 https://molpharm.aspetjournals.org/content/101/3/168.abstract https://www.sciencedirect.com/science/article/pii/S0022202X24002689 https://onlinelibrary.wiley.com/doi/abs/10.1002/adtp.202100149 https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00459/full https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30062-3/fulltext