The Potential for Senolytics and Other Senotherapies to Improve Outcomes in Cancer Therapies

Cellular senescence is a double-edged sword in the matter of cancer. The state of senescence is a growth arrest coupled with pressure to self-destruct and a call to the immune system to destroy the senescent cell. As such it serves as a first line of defense against cancer. Most cancer treatments force large numbers of cancerous cells into senescence, in addition to causing outright cell death, shutting down their ability to replicate. Unfortunately, the presence of too many senescent cells is harmful in and of itself, as their signaling produces chronic inflammation, disrupts tissue function throughout the body, and makes the environment more hospitable for cancer growth.

Thus cancer survivors who undergo chemotherapy or radiotherapy have a reduced life expectancy and greater degree of health issues, including cancer recurrence, as a result of an increased burden of senescent cells. This is a far better outcome than dying of cancer, of course, but it is nonetheless an issue to be dealt with. Now that the research community has identified senolytic drugs capable of selectively destroying a sizable fraction of senescent cells in the body, it is possible to think about both improving the efficacy of existing cancer therapies and minimizing their lingering side-effects.

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

Chemotherapy may cause cell death, often by apoptosis, resulting clinically in tumour regression. It may also cause cellular senescence, leading clinically to tumour stasis (growth arrest). The role of senescence in response to chemotherapy is complicated, however, in that the senescence-associated secretory phenotype (SASP) of senescent cells induced by treatment varies between tissues and cell types, according to the precise senescent stimulus. In particular, some senescent cells secrete exosomes and these may have a tumour promoter function. Consequently, senescence induced by some cancer therapies may be harmful and promote tumour growth.

Whilst cells that undergo apoptosis are permanently removed from a cancer, senescent cells remain and secrete various inflammatory cytokines, which may have both positive and negative impacts. There have been concerns that these senescent cells may resist further chemotherapy damage and be a potential reservoir for recurrence. There is evidence that senescent cells may also be re-programmed to re-enter the cell cycle after certain types of chemotherapy and may acquire a more "stem cell"-like phenotype, which may in turn contribute to tumour regrowth and evolution.

Radiotherapy, which is one of the mainstays of cancer therapy, acts by causing direct DNA damage and has wide ranging impacts on cancer cells mediated by reactive oxygen species. The DNA damage response is triggered and if repair is not possible, cells either die if the damage is severe or enter senescence if less severe. Radiotherapy also triggers an immune response, making the treated cells more immunogenic in a variety of ways. Part of this immunogenicity may be due to the release of SASP factors from senescent cells. Another way in which senescence may be a clinically important part of radiotherapy response is in causing radiation-induced fibrosis. This can be a potentially severe complication of radiotherapy, especially in the lung where pulmonary fibrosis may occur. Senescent cells also appear to be linked to skin fibrosis and ulceration following radiotherapy.

In the context of chemotherapy tolerance, there is evidence that some of the adverse effects of chemotherapy are mediated by the therapy-induced senescent cells which have a pro-inflammatory effects (due to SASP) in a doxorubicin or paclitaxel treated mouse model. Removal of these therapy-induced senescent cells abrogated many of the adverse effects of chemotherapy (reduced fatigue, increased activity levels, reduced cardiac functional impairment). In a separate study, again in a mouse model, the elimination of senescent cells by the use of dasatinib and quercetin, reduced the impact of radiotherapy, improved cardiac function and exercise tolerance, and increased life expectancy. Data in humans are also available that show that higher levels of senescence biomarkers are linked with higher rates of treatment-induced adverse events following doxorubicin chemotherapy.

Senotherapies refers to a group of pharmacological agents that interact with senescent cells to interfere with their pro-aging impacts. There are two main categories: senolytic drugs, which selectively destroy senescent cells and senostatic drugs, which inhibit their function by suppression of their release of SASP factors. Of the two drug groups, senolytics have been more extensively studied and show promise of therapeutic value. These are of particular interest as an adjunct to chemotherapy, where the senolytic drug may be able to target cells induced to become senescent by the cancer. They may also improve treatment resilience. There are several agents under investigation.

It is already recognised that long-term survivors of cancer have increased rates of frailty and reduced longevity, some of which are thought to be due to the direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy). A trial is currently running to assess the impact of senolytic therapy on stem cell transplant survivors using dasatinib and quercetin in a small number of patients and assessing the impact on frailty.

Another important patient group is the elderly with cancer. It is well recognized that treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels. This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery. If use of senolytic therapies could reduce the frailty phenotype and enhance resilience, this would be a major advance in cancer therapies.

Comments

This topic is so interesting. Having read recent reports that some cancer cells can hibernate and protect their destruction from fasting autophageous regimes but then actually be destroyed through anti autophageos methods ( like adminstration of a dose of a leucine suppliment or leucine rich foods) I have come to the conclusion that a diet of up to 48 hours of low leucine and methionine and glucose foods ( so as to induce a moderate interplay of autophagy) followed then by a third day of increasing the leucine intake to halt the autophagy and stress/destroy the cancer cells whilst they hibernate seems to be a worthwhile protocol. In essence this is similar to the Glow15 diet that cycles protein sources. The famous blue zones add in a dose of exercise to futher increase the efficacy of autophagy.

Posted by: Daniel Craver at January 28th, 2021 3:40 PM

What plant foods are rich in methionine? I am a vegetarian

Posted by: Pablo Reinaldos at January 29th, 2021 2:52 AM

Daniel, What about 48 hours of water fasting ( instead of guessing which foods are void if those things) followed by eating or supplementing high leucine to break fast.
This is quite interesting and I'd like to hear more of your thoughts on this.

Posted by: august33 at January 29th, 2021 1:31 PM

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