4 replies to this topic

[OlderThanThou2]

I was reading on FOXO4-DRI, could the same technique be used to inhibit TRF1 to prevent the inhibition of telomerase? The peptide would have to bind to TRF1. Don't know if a peptide can be made to enter the nucleus or if TRF1 can get out of the nucleus to interact with the peptide.

[QuestforLife]

TERF-1 only limits the additions of more TTAGGG units to the end of the telomere, it doesn't actually inhibit the production of telomerase. Its downregulation might increase the length of telomeres due to the low background levels of telomerase in most cells. 

[OlderThanThou2]

Lengthening the telomeres should have positive effects on its own.

 

Here's a study on TRF1 inhibition on cancer growth and general health in mice:

https://www.ncbi.nlm...les/PMC4520658/

 

Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, however, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. Here, we address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf1 ablation impairs the growth of p53-null K-RasG12V-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Long-term whole-body Trf1 deletion in adult mice did not impact on mouse survival and viability, although some mice showed a moderately decreased cellularity in bone marrow and blood. Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function. Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

 

 

They also inhibited TRF1 with tamoxifen:

 

 

 

Then, twelve-week-old Trf1+/+ hUBC-CreERT2 and Trf1lox/lox hUBC-CreERT2 mice were subjected to a tamoxifen-containing diet for 7 weeks in order to induce Trf1 deletion. After this period of time, a total of eight mice of each genotype were sacrificed to analyze the extent of Trf1 deletion in a panel of different tissues as well as to perform full histopathological analysis. qPCR analysis showed that Trf1 had been successfully deleted from heart, intestine, lung, skin, blood, liver, kidney, bone marrow, brain, and stomach (Fig​(Fig6B).6B). 

 

Chart 6B shows a strong inhibition.

 

They also identified 2 chemical compounds capable of inhibiting TRF1. One was tested in vivo and the results were:

 

 

In addition, ET-47037-treated tumors showed a significant decrease in proliferating and mitotic cells and increase in the number of G2-arrested cells (Fig​(Fig9A9A–D). Importantly, during the treatment, the mice showed a normal viability and did not show any signs of sickness. Histopathological analysis of the intestine did not reveal any apparent lesion although we saw increased aberrant mitotic figures and nuclei characteristic of TRF1 inhibition (Fig​(Fig9E).9E). In bone marrow, moderate aplasia, necrotic cells, and hemosiderosis were observed. In the skin, multinucleated cells and giant nuclei were detected (Fig​(Fig9F),9F), a hallmark of TRF1 targeting. Of note, ETP-47037 did not induce changes in telomere length in treated tumors as compared to untreated ones (Fig​(Fig9G).9G). These findings indicate that TRF1 inhibition can be achieved in vivo using chemical compounds and that there is a therapeutic window for targeting TRF1 in cancer that merits further work.

 

The problem is it didn't lengthen the telomeres. 

 

 

Importantly, we demonstrate here that a long-term systemic depletion of TRF1 in healthy adult tissues does not compromise organism viability, although we observed decreased cellularity in some highly proliferative compartments, such as the hematopoietic compartment and blood, which were recovered upon tamoxifen removal. Together, these findings suggest a therapeutic window for TRF1 inhibition in cancer.

 

 

 

This being said, I'm not sure after all that removing the caps of the telomeres wouldn't lead to serious problems, even if there was a way to cause telomere elongation. Could a hit and run strategy like for senolytics be made to work to lengthen the telomeres, like 3 times 1 week of TRF1 inhibition at one month interval? No idea. 

[QuestforLife]

Yeah, I'd pursue other avenues for lengthening telomeres.

[OlderThanThou2]

It sounds dangerous indeed.