Dasatinib

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Dasatinib is a chemotherapeutic drug used for treating certain types of leukaemia[1]. The compound was originally named dasatinib after one of the research fellows who helped produce it, Jagabandhu Das[2].

The chemical structure of dasatinib.

Dasatinib has shown to have senolytic effect in combination with the drug quercetin (D+Q) in both mice and humans[3][4].

Having performed a risk-benefit analysis[5], the Forever Healthy Foundation has decided to "avoid the use of D+Q as a senolytic therapy", until it is more clear what benefits and risks the therapy brings.

Summary of everything below plus additional background information.

Check copyright for the picture (is the attribution enough?)

Evidence of lifespan extension (WIP)

Mice

Following the discovery that mice's healthspan could be extended by killing senescent cells by activating a sucide gene (find source for this and read and cite), a research team led by Zhu et al. found in 2015 that dasatinib in combination with quercetin could...

Since this pioneering study, many have followed and replicated...

https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy+-+Table+3%3A+Preclinical+trials

*Age-related diseases? Other subjects from pre-clinical trials?

Humans

There has been no evidence to date of dasatinib, or dasatinib in combination with quercetin, contributing to life- or health-span extension in humans.

Mechanism (WIP)

Inhibition of tumour growth

Dasatinib is a tyrosine kinase inhibitor. This means that it inhibits tyrosine kinases - abnormal enzymes that help cancer cells to grow uncontrollably. In particular,

Tyrosine kinases are especially prevalent in patients with chronic myeloid leukaemia (CML), of which most[6] have a so-called Philadelphia chromosome1, which is why dasatinib is used mainly for treating CML (see more below).

Note: A 90% figure can be found in the following source - however, I cannot get access to it:

Nowell, P. C. & Hungerford, D. A. (1960) Science 132, 1947.

Questions to answer: How do tyrosine kinases help cancer cells grow uncontrollably?

Reducing cellular senescence

The first time dasatinib was used as a senolytic was in 2015, when a research team led by Zhu et al. screened for potential drugs to stop the SCAPs...

Dasatinib works as a senolytic in combination with quercetin by targeting senescent human adipocyte progenitors - early versions of fat cells (Q, on the other hand, targets senescent cultured HUVEC's). They disable networks of SCAPs and thus induces apoptosis, cell death.

Working question: Why, and how, does dasatinib target fat cells exactly? Same for quercetin and HUVECs.

"...neither D nor Q are senolytic on their own, whilst the combination of D + Q is senolytic"[7]


WORK IN PROGRESS SPACE

"senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL"[8]

"D promotes apoptosis caused by dependence receptors, such as the ephrins, in part by inhibiting Src kinase [88, 89]"[7]

ABL1 and SRC family kinases

How does D promote apoptosis?

https://pubmed.ncbi.nlm.nih.gov/21528941/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931551/

"Based on their known targets, we predicted that D would target senescent human cultured primary adipocyte progenitor cells, whilst Q would target senescent cultured HUVEC’s. These predictions proved to be correct. The combination of D + Q caused apoptosis of both senescent human primary adipocyte progenitor cells and senescent HUVEC’s, but not nonsenescent adipocyte progenitor cells or HUVEC’s. Furthermore, likely because of redundancy of SCAP pathways, in some cell types, for example, mouse embryonic fibroblasts, neither D nor Q are senolytic on their own, whilst the combination of D + Q is senolytic"[7]

"senescent HUVECs were more susceptible to EFNB1 and BCL-xL siRNAs than nonsenescent cells"[9]

LAST LEFT: [7]

"Of these, six triggered senescent cell death, but had little effect on proliferating, nonsenescent cells in two human cell types, preadipocytes (Fig. 1D,F) and endothelial cells (Fig. 1E,G)"[9]

"known to interfere with EFNB-dependent suppression of apoptosis"[9]

"D preferentially reduced viability and caused cell death of senescent human preadipocytes"[9]

Why are human adipocyte progenitors and endothelial cells (HUVECs) important classes of senescent cells? What are the other types?

For longevity, not in general.

Human clinical trials

As of May 2020 there have been three human clinical trials using dasatinib in combination with quercetin (D+Q) as a senolytic[10].

The findings of the first ever clinical trial using senolytics in humans was published in December 2018. This pilot study indicated that D+Q may alleviate some of the physical dysfunction experienced by individuals with idiopathic pulmonary fibrosis (IPF), suggesting feasibility of larger, controlled trials evaluating senolytic treatment in IPF and other senescence-associated diseases[11].

A study published in July 2019 showed slight improvement of cardiovascular function in male individuals 21 days after receiving doses of D+Q[12].

Finally, a preliminary report published in August 2019 showed that intake of D+Q decreased the number of senescent cells in the body fat of individuals with diabetic kidney disease[3][13], a condition characterised by senescent cell burden[14]. This is the first and only study to date that has shown a direct effect between senolytic drug treatment and decreased abundance of senescent cells in humans.

Further clinical trials using D+Q as senolytics are on their way, for example investigating their effect on skeletal health, and the progression of Alzheimer's Disease[15].

Regulatory Approval

Dasatinib was approved by the US Food and Drug Administration (FDA) in 2006, for the purpose of treating "adults with chronic myeloid leukemia with resistance or intolerance to prior therapy including imatinib"[16], and has been marketed under the brand name Sprycel. Sprycel was similarly approved by the European Medicines Agency (EMA) in the same year[17].

Safety (WIP)

There has been plenty of studies on the side effects of dasatinib[18].

https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021986lbl.pdf, Page 30

Studies indicate that intermittent administration of dasatinib, and senolytics in general, may circumvent potential off-target effects[19].

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395/ - these state this, too.)

Current use in medicine

Dasatinib is used to treat Philadelphia-chromosome-positive (Ph+) chronic myeloid leukaemia, sometimes after previous treatment with imatinib has failed. Patients with Ph+ acute lymphoblastic leukaemia (ALL) for which this is also the case, dasatinib can also be used. It is taken orally[1].

Dasatinib is on the list of the World Health Organization's List of Essential Medicines[20].

Footnotes

1 The Philadelphia chromosome is formed when the ABL1 gene on chromosome 9 breaks off and translocates to the BCR gene on chromosome 22, forming a fusion gene called BCR-ABL1[21]. This new fusion gene instructs cells to produce tyrosine kinases, which in turn permanently "turns on" important cell switches controlling cell division, growth and cell death

LAST UPDATE (20210630):

Q: How does tyrosine kinases help cancer cells? Tyrosine kinase in cancer - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1074718/

Q: How does the BCR-ABL1 gene instruct cells to product tyrosine kinases?

Move this information to mechanism later on?

References (WIP)

Fix this section using APA referencing.

  1. 1.0 1.1 https://www.drugs.com/monograph/dasatinib.html?references=1
  2. http://cenblog.org/the-haystack/2012/01/jagabandhu-das-dasatinib/
  3. 3.0 3.1 https://linkinghub.elsevier.com/retrieve/pii/S2352396419305912
  4. https://onlinelibrary.wiley.com/doi/10.1111/acel.12344
  5. https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy
  6. https://www.cancerresearchuk.org/about-cancer/chronic-myeloid-leukaemia-cml/about
  7. 7.0 7.1 7.2 7.3 https://onlinelibrary.wiley.com/doi/10.1111/joim.13141
  8. https://www.nature.com/articles/ncomms11190
  9. 9.0 9.1 9.2 9.3 https://onlinelibrary.wiley.com/doi/10.1111/acel.12344
  10. https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy
  11. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30629-7/fulltext
  12. https://www.jbiomeds.com/biomedical-sciences/dasatinib-and-quercetin-shortterm-simultaneous-administration-improves-physical-capacity-in-human.php?aid=24542
  13. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30810-2/fulltext
  14. https://pubmed.ncbi.nlm.nih.gov/18768588/
  15. https://clinicaltrials.gov/ct2/results?cond=&term=dasatinib+AND+quercetin&cntry=&state=&city=&dist=
  16. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021986s000ltr.pdf
  17. https://www.ema.europa.eu/en/medicines/human/EPAR/sprycel
  18. https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy+-+Table+2%3A+Clinical+Trials
  19. https://linkinghub.elsevier.com/retrieve/pii/S2352396419305912
  20. https://apps.who.int/iris/handle/10665/330668
  21. https://www.sciencedirect.com/science/article/pii/S0304419X01000221?via%3Dihub#BIB7