HSP90 Inhibitors as Another New Class of Potential Senolytic Drug Compounds

The increasing number of senescent cells present in older tissues is one of the root causes of degenerative aging. It is also the closest to being effectively reversed. An open access paper describing the evidence for HSP90 inibitors to selectively destroy senescent cells was published earlier this month. I had half missed it in passing and half skipped over it in favor of a more general review of the current state of senolytic drug development, pharmaceuticals capable of clearing senescent cells, but on reflection I think it is worth pointing out. The number of senolytic drug candidates has not yet reached a count of twenty, and some of them are probably not all that great, such as quercetin and fisetin, while others are chemotherapeutics with enough in the way of ugly side-effects to be avoided if there is a choice in the matter. So new categories of potential senolytics are worth noting.

Like many classes of drug candidates, HSP90 inhibitors have been considered for use against cancer. There is a strong connection between the phenomenon of cellular senescence and cancer research, through scientists in that field have generally been interested in generating more senescent cells rather than fewer of them. They are trying to push tumor cells and potentially cancerous cells into becoming senescent rather than replicating rampantly, enhancing the natural function of of cellular senescence as a means to reduce cancer risk. Unfortunately, the fact that chemotherapeutics generate a high load of senescent cells in patients, either intentionally or because they are toxic to cells in general, is one of the reasons why chemotherapy is so damaging to long term health even when successful. There are other points of connection as well: cancer researchers are also interested in pushing abnormal cells into programmed cell death processes such as apoptosis, and selectively triggering apoptosis in senescent cells is the goal of all senolytic drug candidates to date. So we should certainly expect to see new senolytic pharmaceuticals to have been evaluated as cancer therapies at some point in the past.

Are HSP90 inhibitors any good in comparison to the other types of senolytic discovered to date? I'd say it is far too early to do any more than handwave this sort of comparison. The results from animal studies to date suggest that candidate senolytics fall into one of two broad categories: they either do little to senescent cells, or they clear up to 50% of these cells, that effectiveness varying by tissue type, drug candidate, and dosage. Different drugs in the same general category of senolytics can have very different outcomes. This sort of variation is in evidence in the data from progeroid mice in this study, which at least puts a few HSP90 inhibitors, geldanamycin and 17-AAG / tanespimycin, into the category of "clears senescent cells" rather than "does nothing" - the results in mice look something like 50% clearance in the kidney versus 25% in the liver, on a par with the best of the other present drug candidates with published animal data.

Identification of HSP90 inhibitors as a novel class of senolytics

Replicative senescence is a cellular program preventing further cell divisions once telomeres become critically short. Senescence also can be induced by cellular stress, including oxidative and genotoxic stresses, or by activation of certain oncogenes. Senescent cells secrete pro-inflammatory factors, metalloproteinases, and other proteins, collectively termed the senescence-associated secretory phenotype (SASP). With chronological aging, there is an accumulation of senescent cells in mammals. This is thought to drive senescence of neighboring cells via the SASP and the functional decline of tissues.

Clearance of senescent cells rodent models restored vascular reactivity, stabilized atherosclerotic plaques, improved pulmonary function, alleviated osteoarthritis, and improved fatty liver disease. Thus, the increase in cellular senescence that occurs with aging appears to play a major role in driving life-limiting age-related diseases. Therefore, therapeutic approaches to specifically kill senescent cells have the potential to extend healthspan and lifespan.

Using a bioinformatics approach, we recently identified several pro-survival pathways, including the Bcl-2/Bcl-XL, p53/p21, PI3K/AKT, and serpine anti-apoptotic pathways that, when inhibited, result in death of senescent murine and human cells. A combination of the drugs dasatinib and quercetin, which target several of these pro-survival pathways, induce death specifically in senescent murine and human cells. Similarly, we and others also demonstrated that several inhibitors of Bcl-2 family members like navitoclax (ABT263), A1331852 and A1155463 are senolytic in some, but not all cell types. In addition, a FOXO4-interacting peptide that blocks an association with p53 recently was demonstrated to induce apoptosis in senescent cells.

Here, we describe the development of a novel screening platform to identify senotherapeutics, drugs that either suppress senescence (senomorphics) or selectively kill senescent cells (senolytics). The screen utilizes DNA repair deficient Ercc1-/- primary murine embryonic fibroblasts (MEFs), which senesce rapidly when grown at atmospheric oxygen, and detection of senescence-associated β-galactosidase (SA-β-gal). Using this platform to screen a library of autophagy regulators, a process known to influence the senescence phenotype of different cell types, we identified HSP90 inhibitors as a novel class of senolytic agents, able to induce apoptosis of senescent cells specifically.

To validate the platform, HSP90 inhibitors were tested for senolytic activity in human cells in culture and in a progeroid mouse model of accelerated aging, where the intervention delayed multiple age-related comorbidities. These results demonstrate the utility of the screening platform for identifying novel classes of senotherapeutics. Furthermore, the results demonstrate that an HSP90 inhibitor used clinically is senolytic and could be potentially repurposed to extend healthspan.

Comments

It was good to see other targets for senolytics emerge yes, but HSP90?
I like my mitochondrial import the way it is, and severel HSP90 isoforms, particularly the cytosolic guys, are involved in coordinating import at TOMs. Thats why our cells still keep these HSPs constituitively active to the tune of 2% total cell protein, only bumping up to 4% total protein when needed. Thats a lot of inhibitor. Hopefully the inhibitors leave the other import related HSP families (like HSP) alone at least.
https://www.ncbi.nlm.nih.gov/pubmed/12526792

Posted by: john hewitt at September 19th, 2017 9:44 AM

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