Longevity Wiki - User contributions [en-GB]

Dasatinib

2021-07-07T08:29:30Z

SimonHolm97: Added categories Drugs, Senolytics to the article.

Dasatinib is a chemotherapeutic drug used for treating certain types of leukaemia<ref name=":0">https://www.drugs.com/monograph/dasatinib.html?references=1</ref>. The compound was originally named dasatinib after one of the research fellows who helped produce it, Jagabandhu Das<ref name=":1">http://cenblog.org/the-haystack/2012/01/jagabandhu-das-dasatinib/</ref>.
[[File:Dasatinib ball-and-stick molecule.png|thumb|The chemical structure of dasatinib.]]
Dasatinib has shown to have [[Senolytics|senolytic]] effect in combination with the drug [[quercetin]] (D+Q) in both mice and humans<ref name=":3">https://linkinghub.elsevier.com/retrieve/pii/S2352396419305912</ref><ref>https://onlinelibrary.wiley.com/doi/10.1111/acel.12344</ref>.

Having performed a risk-benefit analysis<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy</ref>, 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<ref>https://www.cancerresearchuk.org/about-cancer/chronic-myeloid-leukaemia-cml/about</ref> 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"<ref name=":5">https://onlinelibrary.wiley.com/doi/10.1111/joim.13141</ref>
----WORK IN PROGRESS SPACE

"senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL"<ref>https://www.nature.com/articles/ncomms11190</ref>

"D promotes apoptosis caused by dependence receptors, such as the ephrins, in part by inhibiting Src kinase [88, 89]"<ref name=":5" />

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"<ref name=":5" />

"senescent HUVECs were more susceptible to EFNB1 and BCL-xL siRNAs than nonsenescent cells"<ref name=":6">https://onlinelibrary.wiley.com/doi/10.1111/acel.12344</ref>

LAST LEFT: <ref name=":5" />

"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)"<ref name=":6" />

"known to interfere with EFNB-dependent suppression of apoptosis"<ref name=":6" />

"D preferentially reduced viability and caused cell death of senescent human preadipocytes"<ref name=":6" />

''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<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy</ref>.

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<ref name=":4">https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30629-7/fulltext</ref>.

A study published in July 2019 showed slight improvement of cardiovascular function in male individuals 21 days after receiving doses of D+Q<ref name=":2">https://www.jbiomeds.com/biomedical-sciences/dasatinib-and-quercetin-shortterm-simultaneous-administration-improves-physical-capacity-in-human.php?aid=24542</ref>.

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<ref name=":3" /><ref>https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30810-2/fulltext</ref>, a condition characterised by senescent cell burden<ref>https://pubmed.ncbi.nlm.nih.gov/18768588/</ref>. 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<ref>https://clinicaltrials.gov/ct2/results?cond=&term=dasatinib+AND+quercetin&cntry=&state=&city=&dist=</ref>.

== 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"<ref>https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021986s000ltr.pdf</ref>, and has been marketed under the brand name Sprycel. Sprycel was similarly approved by the European Medicines Agency (EMA) in the same year<ref>https://www.ema.europa.eu/en/medicines/human/EPAR/sprycel</ref>.

== Safety (WIP) ==
There has been plenty of studies on the side effects of dasatinib<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy+-+Table+2%3A+Clinical+Trials</ref>.

[https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021986lbl.pdf 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<ref>https://linkinghub.elsevier.com/retrieve/pii/S2352396419305912</ref>.

(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<ref name=":0" />.

Dasatinib is on the list of the World Health Organization's List of Essential Medicines<ref>https://apps.who.int/iris/handle/10665/330668</ref>.

== 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''<ref>https://www.sciencedirect.com/science/article/pii/S0304419X01000221?via%3Dihub#BIB7</ref>. 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.<references />
[[Category:Longevity]]
[[Category:Senolytics]]
[[Category:Drugs]]

Dasatinib

2021-06-30T16:53:12Z

SimonHolm97: Made a bit more reading on tyrosine kinases, trying to make sense how they contribute to cancer, and hence how dasatinib helps preventing it.

Dasatinib

2021-06-23T16:02:40Z

SimonHolm97: Worked on reducing cellular senescence, trying to get to the bottom of the exact mechanism behind dasatinib and quercetin in inducing apoptosis/disabling SCAP networks.

Dasatinib is a chemotherapeutic drug used for treating certain types of leukaemia<ref name=":0">https://www.drugs.com/monograph/dasatinib.html?references=1</ref>. The compound was originally named dasatinib after one of the research fellows who helped produce it, Jagabandhu Das<ref name=":1">http://cenblog.org/the-haystack/2012/01/jagabandhu-das-dasatinib/</ref>.
[[File:Dasatinib ball-and-stick molecule.png|thumb|The chemical structure of dasatinib.]]
Dasatinib has shown to have [[Senolytics|senolytic]] effect in combination with the drug [[quercetin]] (D+Q) in both mice and humans<ref name=":3">https://linkinghub.elsevier.com/retrieve/pii/S2352396419305912</ref><ref>https://onlinelibrary.wiley.com/doi/10.1111/acel.12344</ref>.

Having performed a risk-benefit analysis<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy</ref>, 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 lifespan extension in humans.

== Mechanism (WIP) ==

=== Inhibition of tumour growth ===
The main function of dasatinib is to inhibit ''tyrosine kinases'' - abnormal enzymes that help cancer cells to grow uncontrollably (no good source for this! See 'Current Use in Medicine' below). Tyrosine kinases are especially prevalent in patients with chronic myeloid leukaemia (CML), of which most<ref>https://www.cancerresearchuk.org/about-cancer/chronic-myeloid-leukaemia-cml/about</ref> 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.

=== 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"<ref name=":5">https://onlinelibrary.wiley.com/doi/10.1111/joim.13141</ref>
----WORK IN PROGRESS SPACE

"senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL"<ref>https://www.nature.com/articles/ncomms11190</ref>

"D promotes apoptosis caused by dependence receptors, such as the ephrins, in part by inhibiting Src kinase [88, 89]"<ref name=":5" />

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"<ref name=":5" />

"senescent HUVECs were more susceptible to EFNB1 and BCL-xL siRNAs than nonsenescent cells"<ref name=":6">https://onlinelibrary.wiley.com/doi/10.1111/acel.12344</ref>

LAST LEFT: <ref name=":5" />

"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)"<ref name=":6" />

"known to interfere with EFNB-dependent suppression of apoptosis"<ref name=":6" />

"D preferentially reduced viability and caused cell death of senescent human preadipocytes"<ref name=":6" />

''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<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy</ref>.

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<ref name=":4">https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30629-7/fulltext</ref>.

A study published in July 2019 showed slight improvement of cardiovascular function in male individuals 21 days after receiving doses of D+Q<ref name=":2">https://www.jbiomeds.com/biomedical-sciences/dasatinib-and-quercetin-shortterm-simultaneous-administration-improves-physical-capacity-in-human.php?aid=24542</ref>.

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<ref name=":3" /><ref>https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30810-2/fulltext</ref>, a condition characterised by senescent cell burden<ref>https://pubmed.ncbi.nlm.nih.gov/18768588/</ref>. 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<ref>https://clinicaltrials.gov/ct2/results?cond=&term=dasatinib+AND+quercetin&cntry=&state=&city=&dist=</ref>.

== 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"<ref>https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021986s000ltr.pdf</ref>, and has been marketed under the brand name Sprycel. Sprycel was similarly approved by the European Medicines Agency (EMA) in the same year<ref>https://www.ema.europa.eu/en/medicines/human/EPAR/sprycel</ref>.

== Safety (WIP) ==
There has been plenty of studies on the side effects of dasatinib<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy+-+Table+2%3A+Clinical+Trials</ref>.

[https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021986lbl.pdf 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<ref>https://linkinghub.elsevier.com/retrieve/pii/S2352396419305912</ref>.

(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<ref name=":0" />.

Dasatinib is on the list of the World Health Organization's List of Essential Medicines<ref>https://apps.who.int/iris/handle/10665/330668</ref>.

== 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''. 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

(I can't find a good source for this, the closest being section 4 in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1074718/ OR https://cancercommun.biomedcentral.com/articles/10.1186/s40880-016-0108-0).

== References (WIP) ==
Fix this section using APA referencing.<references />

Dasatinib

2021-06-22T16:24:13Z

SimonHolm97: Put the information about the Philadelphia chromosome as a footnote; added that dasatinib is taken orally. Started writing on initial studies on mice.

Dasatinib is a chemotherapeutic drug used for treating certain types of leukaemia<ref name=":0">https://www.drugs.com/monograph/dasatinib.html?references=1</ref>. The compound was originally named dasatinib after one of the research fellows who helped produce it, Jagabandhu Das<ref name=":1">http://cenblog.org/the-haystack/2012/01/jagabandhu-das-dasatinib/</ref>.
[[File:Dasatinib ball-and-stick molecule.png|thumb|The chemical structure of dasatinib.]]
Dasatinib has shown to have [[Senolytics|senolytic]] effect in combination with the drug [[quercetin]] (D+Q) in both mice and humans<ref name=":3">https://linkinghub.elsevier.com/retrieve/pii/S2352396419305912</ref><ref>https://onlinelibrary.wiley.com/doi/10.1111/acel.12344</ref>.

Having performed a risk-benefit analysis<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy</ref>, 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 lifespan extension in humans.

== Mechanism (WIP) ==

=== Inhibition of tumour growth ===
The main function of dasatinib is to inhibit ''tyrosine kinases'' - abnormal enzymes that help cancer cells to grow uncontrollably (no good source for this! See 'Current Use in Medicine' below). Tyrosine kinases are especially prevalent in patients with chronic myeloid leukaemia (CML), of which most<ref>https://www.cancerresearchuk.org/about-cancer/chronic-myeloid-leukaemia-cml/about</ref> 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.

=== 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...

LAST LEFT: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395/

https://onlinelibrary.wiley.com/doi/10.1111/acel.12344

"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)"

"known to interfere with EFNB-dependent suppression of apoptosis"

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

Dasatinib works as a senolytic by disabling networks of SCAPS in senescent human adipocyte progenitors.

''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<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy</ref>.

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<ref name=":4">https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30629-7/fulltext</ref>.

A study published in July 2019 showed slight improvement of cardiovascular function in male individuals 21 days after receiving doses of D+Q<ref name=":2">https://www.jbiomeds.com/biomedical-sciences/dasatinib-and-quercetin-shortterm-simultaneous-administration-improves-physical-capacity-in-human.php?aid=24542</ref>.

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<ref name=":3" /><ref>https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30810-2/fulltext</ref>, a condition characterised by senescent cell burden<ref>https://pubmed.ncbi.nlm.nih.gov/18768588/</ref>. 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<ref>https://clinicaltrials.gov/ct2/results?cond=&term=dasatinib+AND+quercetin&cntry=&state=&city=&dist=</ref>.

== 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"<ref>https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021986s000ltr.pdf</ref>, and has been marketed under the brand name Sprycel. Sprycel was similarly approved by the European Medicines Agency (EMA) in the same year<ref>https://www.ema.europa.eu/en/medicines/human/EPAR/sprycel</ref>.

== Safety (WIP) ==
There has been plenty of studies on the side effects of dasatinib<ref>https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy+-+Table+2%3A+Clinical+Trials</ref>.

[https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021986lbl.pdf 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<ref>https://linkinghub.elsevier.com/retrieve/pii/S2352396419305912</ref>.

(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<ref name=":0" />.

Dasatinib is on the list of the World Health Organization's List of Essential Medicines<ref>https://apps.who.int/iris/handle/10665/330668</ref>.

== 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''. 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

(I can't find a good source for this, the closest being section 4 in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1074718/ OR https://cancercommun.biomedcentral.com/articles/10.1186/s40880-016-0108-0).

== References (WIP) ==
Fix this section using APA referencing.<references />

Dasatinib

2021-06-20T11:14:04Z

SimonHolm97: Working on the Mechanism section, I now try to find out why human preadipocytes and HUVECs are used in the study of cellular senescence, and not other types of cells, since it seems like this founds the basis of using dasatinib and quercetin as senolytics.

Cellular senescence

2021-06-08T15:45:39Z

SimonHolm97: Created the article and wrote down everything I have learned from doing research on the dasatinib article.

Cellular senescence is one of the [[Hallmarks of Aging|hallmarks of aging]].

== Mechanism ==
''Question to writers: Cellular senescence seems to have a positive function in our bodies - what is that? How does it become dangerous? It seems like it is "a normally adaptive response to injury or infection". Source: <nowiki>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941545/</nowiki>''

Senescent cells secrete a phenotype, appropriately called ''senescence-associated secretory phenotype'' (SASP), which releases various factors that cause inflammation and dysfunction and promotes apoptosis (cell death) in nearby tissues.

''Source references are needed for all of the above, for example:''

https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy

=== Diseases associated with cellular senescence ===
Due to the SASP, senescent cells have been associated with a number of age-related diseases:

<nowiki>*</nowiki>Fibrotic Pulmonary Disease: <nowiki>https://pubmed.ncbi.nlm.nih.gov/28230051/</nowiki>

== Senolytics ==
''See the full article on [[senolytics]].''

Senescent cells survive their own SASP, since they are protected by networks of ''senescent cell anti-apoptotic pathways'' (SCAPs). One method of senolytics, therefore, is to interfere with these networks, so that the SASP also induce apoptosis in the senescent cells themselves.

Senescent cells take time to re-build once they are ablated. Hence, an advantage of senolytic treatment is that it can be done in a "hit-and-run" fashion, thus avoiding off-target effects in comparison to other types of treatments.

A way to track if senolytics have any effect is to check out for ''senescent biomarkers''. It seems like p16, p21 and senescence-associated β-galactosidase activity (SA-β-gal) are known markers of senescent cells.

''Writers: Make sure to sync this article with senolytics.''

''Source references are needed for all of the above, see for example the three human clinical trial studies in the article on [[dasatinib]].''

== Negligible senescence ==
''See the full article on [[negligible senescence]].''

The phenomenon of showing no signs of senescence, such as age-related dysfunctions (Wikipedia).

Dasatinib

2021-06-08T15:29:49Z

SimonHolm97: Moved a section on cellular senescence to the article about cellular senescence

Hallmarks of aging

2021-06-08T15:25:18Z

SimonHolm97: Made a reference to the ARTICLE of cellular senescence (as I assume it deserves its own article).

Aging is not a single process but is composed of a complex group of interconnected cellular events. The hallmarks of aging are the basic processes underlying aging in different organisms. These hallmarks are associated with major diseases such as cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. In a now widely-cited [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ 2013 research paper], nine tentative hallmarks were proposed.

== Genomic instability ==
The genome is the total sum of DNA in our body and becomes damaged over time, and genomic instability leading to age-related problems. DNA which carries the information to make proteins that make up cells and tissues.

DNA damage may be caused by UV radiation, X-ray radiation, chemical toxins such as tobacco. The damage can also occur due to normal chemical reactions in our body, known as metabolism, create products (reactive oxygen species) that damage the DNA.

While the body has evolved repair systems to deal with the DNA damage as it arises and special proteins (enzymes) detect and repair broken strands of the DNA. However, the DNA repair processes are not perfect and errors in the DNA (mutations) arise over time. The body generally deals with these cells containing too many mutations through a kind of programmed cell suicide known as apoptosis. These senescent cells result in further age-related problems.

== Telomere Attrition ==
Each time a cell divides, the telomeres or ‘caps’ at the ends of the chromosomes shorten. Once the telomeres become too short, the cell may no longer function correctly.

== Epigenetic alterations ==
The epigenome is the system that turns genes on or off. This system becomes dysregulated over time, resulting in incorrect expression of genes.

== Loss of proteostasis ==
Cells and tissues require a fine balance of different proteins to function correctly. This equilibria becomes dysregulated over time, as organelles such as the lysosome lose functionality.

== Deregulated nutrient-sensing ==
Key pathways involved in metabolism such as mTOR, IGF-1 and AMPK are central to the aging process, and become dysregulated over time.

== Mitochondrial dysfunction ==
Mitochondria are the ‘powerhouses’ of the cell, and lose functionality over time.

== Cellular senescence ==
''See the full article on [[cellular senescence]].''

Cells become senescent, resisting death and secreting proinflammatory factors. These cells accumulate and infect other cells over time to progressively drive aging throughout the body.

== Stem cell exhaustion ==
stem cells are immature cells that can differentiate into cells for many types of tissue - for example brain, heart and lung cells. Stem cell production declines over time, causing tissues to degenerate.

Dasatinib

2021-06-08T15:21:04Z

SimonHolm97: Finished section on human clinical trials for now, partly by adding a summary of the IPF study.

Dasatinib

2021-06-07T11:51:11Z

SimonHolm97: Started working on the Mechanism section - trying to figure out why dasatinib is in combination with quercetin

Dasatinib

2021-05-13T17:57:29Z

SimonHolm97: Added information to "Current use in medicine" and "Regulatory Approval" and a few other sentences.

Dasatinib

2021-05-13T06:58:45Z

SimonHolm97: Added source to further read on ongoing human clinical trials.

Dasatinib is a chemotherapeutic drug used for treating certain types of leukaemia<ref>https://www.drugs.com/monograph/dasatinib.html?references=1</ref>. The compound was originally named dasatinib after one of the research fellows who helped produce it, Jagabandhu Das<ref>http://cenblog.org/the-haystack/2012/01/jagabandhu-das-dasatinib/</ref>.

*[[File:Dasatinib ball-and-stick molecule.png|thumb|The chemical structure of dasatinib.]]Dasatinib has shown to (life extension stuff, connect with heading below, use the word [[Senolytics|senolytic]])...together with quercetin (D+Q)

The Forever Healthy Foundation has issued a recommendation to "not use DQ as a senolytic therapy", having performed a risk-benefit analysis.

Good source for information: https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy

== Evidence of lifespan extension ==

=== Mice ===

=== Humans ===

== Mechanism ==
For longevity, not in general.

== Human clinical trials ==

Further clinical trials are on their way, and new results from X different studies on Y and Z are expected in the next A years.

https://clinicaltrials.gov/ct2/results?cond=&term=dasatinib+AND+quercetin&cntry=&state=&city=&dist=

== Regulatory Approval ==
Brand names (Sprycel)?

== Safety ==

== Current use in medicine ==

== References ==
Fix this section using APA referencing.<references />

Dasatinib

2021-05-10T16:46:43Z

SimonHolm97: Found and added source reference for the origin of the name. Added temporary sentence for next edit.

Dasatinib is a chemotherapeutic drug used for treating certain types of leukaemia<ref>https://www.drugs.com/monograph/dasatinib.html?references=1</ref>. The compound was originally named dasatinib after one of the research fellows who helped produce it, Jagabandhu Das<ref>http://cenblog.org/the-haystack/2012/01/jagabandhu-das-dasatinib/</ref>.

*[[File:Dasatinib ball-and-stick molecule.png|thumb|The chemical structure of dasatinib.]]Dasatinib has shown to (life extension stuff, connect with heading below, use the word [[Senolytics|senolytic]])...together with quercetin (D+Q)

The Forever Healthy Foundation has issued a recommendation to "not use DQ as a senolytic therapy", having performed a risk-benefit analysis.

Good source for information: https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy

== Evidence of lifespan extension ==

=== Mice ===

=== Humans ===

== Mechanism ==
For longevity, not in general.

== Human clinical trials ==

== Regulatory Approval ==
Brand names (Sprycel)?

== Safety ==

== Current use in medicine ==

== References ==
<references />

Dasatinib

2021-05-09T07:40:21Z

SimonHolm97: Implemented article structure, added picture of chemical structure, started writing on introduction.

Dasatinib is a chemotherapeutic drug, mainly used for treating certain types of leukemia<ref>https://www.drugs.com/monograph/dasatinib.html?references=1</ref>.
*Dasatinib has its name from...

*[[File:Dasatinib ball-and-stick molecule.png|thumb|The chemical structure of dasatinib.]]Dasatinib has shown to (life extension stuff, connect with heading below, use the word [[Senolytics|senolytic]])...

== Evidence of lifespan extension ==

=== Mice ===

=== Humans ===

== Mechanism ==
For longevity, not in general.

== Human clinical trials ==

== Regulatory Approval ==

== Safety ==

== Current use in medicine ==

== References ==
<references />

File:Dasatinib ball-and-stick molecule.png

2021-05-09T07:16:08Z

SimonHolm97:

The chemical structure of dasatinib.