Reversal of Apalutamide and Darolutamide Aldo-Keto Reductase 1C3-Mediated Resistance by a Small Molecule Inhibitor. 2020 Mar 3

[JLS1]

I think this is saying that adding an AKR1C3 inhibitor will prevent resistance to Darolutamide and Apalutamide so that they WILL work for CRPC patients?? If so, I wonder what that add on drug would be??

ncbi.nlm.nih.gov/pubmed/321...

ACS Chem Biol. 2020 Mar 3. doi: 10.1021/acschembio.0c00069. [Epub ahead of print]

Reversal of Apalutamide and Darolutamide Aldo-Keto Reductase 1C3-Mediated Resistance by a Small Molecule Inhibitor.

Morsy A, Trippier PC.

Abstract

The anti-androgen therapeutics Apalutamide and Darolutamide entered the clinic in 2018 and 2019 respectively for the treatment of castration-resistant prostate cancer (CRPC). Increased expression of the enzyme aldo-keto reductase 1C3 (AKR1C3) is phenotypic of CRPC. The enzyme acts to circumvent castration by producing potent androgens that drive proliferation. Furthermore, AKR1C3 mediates chemotherapeutic resistance to the standard of care; Enzalutamide, a structural analogue of Apalutamide. Resistance develops in almost all CRPC patients with three months of beginning treatment. Herein, we report both Apalutamide and the structurally distinct Darolutamide, induce AKR1C3 expression in in vitro models of prostate cancer and are susceptible to AKR1C3-mediated resistance. This effect is countered by pretreatment with a potent and highly selective AKR1C3 inhibitor, sensitizing high AKR1C3 expressing prostate cancer cell lines to the action of both chemotherapeutics with a concomitant reduction in expression of AKR1C3 and the biomarker prostate-specific antigen.

PMID:

32125151

DOI:

10.1021/acschembio.0c00069

[tango65]

It seems it works in cell cultures., It is interesting that they say apalutamide and darolutamide induce ARK1C3: expression.

Link to the full article:

sci-hub.tw/https://pubs.acs...

I hope it will work. Thanks for posting.

Best of luck on this journey.!

[JLS1 in reply to tango65]

Thank you for the full article link! So the question is, what is the drug they'd use - is it available now?

[tallguy2]

Thanks for posting this.

[kaptank]

One AKR1C3 inhibitor known to a few of us here is the NSAID, Indomethacin. There has been "suggestive" work suggesting it may reverse resistance in Abi and Enza. I don't know if that is the drug they are referring to. Some other, over the counter, AK1C3 inhibitors are: red reishi mushroom, green tea, black cohosh and quercitin.

[JLS1 in reply to kaptank]

Do you know if there are any AKR1C3 inhibitors that don't interfere with blood counts, esp platelets? Each of the ones you mentioned can cause low platelets, which could be dangerous to my husband who has a seriously low platelet count.

[kaptank in reply to JLS1]

Indomethacin is by far the most powerful and selective. I don't know how any of them affect blood counts. My doc didn't mention platelets when listing the possible side effects of indo, but it's not a great problem for me. Indo is an old NSAID with a risk profile not unlike ibuprofen, to which it is chemically related. It's often prescribed for arthritic pain and most docs would know about it from that angle. You would need a prescription for indo so maybe ask your ordinary doc.

[JLS1 in reply to kaptank]

Are you currently taking Indomethacin to 'reactivate' Zytiga or Xtandi? If so, for how long?

[kaptank in reply to JLS1]

No, I take it with bicalutamide which seems to have similar AKR1c3 resistance pathways to abi and enza. I haven't been taking it for long and can't tell whether it has had any effect. And I'm taking a bunch of other stuff which may or may not help. I also take it as an anti-inflammatory among a cocktail of other anti inflammatories.

[JLS1 in reply to kaptank]

I just found something that sounds like it works even better - KV-37

mct.aacrjournals.org/conten...

see my post below

[kaptank]

One other aspect of Indo is that it is highly selective. It only inhibits AKR1C3. There are other aldo ketone reductases that perform essential functions and we do not want them inhibited. Most AKR inhibitors are not so selective.

[JLS1]

It sounds like KV-37 is an even better AKR1C3 inhibitor better than Indomethacin! - and somewhere in the article I'm 99% sure I read there were NO adverse side effects!! This is from Sept 2018. I hope there's a way to get this, now! :

mct.aacrjournals.org/conten...

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Small Molecule Therapeutics

AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

Kshitij Verma, Nehal Gupta, Tianzhu Zang, Phumvadee Wangtrakluldee, Sanjay K. Srivastava, Trevor M. Penning and Paul C. Trippier

DOI: 10.1158/1535-7163.MCT-17-1023 Published September 2018

"INDO displays diminished cell viability reduction and a weak synergistic drug action compared with the more potent inhibitor KV-37

INDO (AKR1C3 Ki = 8 μmol/L for the E.NADPH.Indomethacin complex) has been shown to reverse ENZ resistance in prostate cancer models (27). The dose–response curve of INDO showed a weak inhibition of cell viability at 96-hour incubation, IC50 = 112.8 μmol/L (Supplementary Fig. S8A). Further, we also administered INDO as a 24-hour pretreatment to LNCaP1C3 cells followed by ENZ exposure for 72 hours. A moderate synergistic drug action was observed (CI = 0.32; DRI = 6.4; Supplementary Fig. S8B) as compared with the very high degree of synergism with KV-37 under identical conditions (CI = 0.14; DRI = 24.8). These findings further bolster the concept that AKR1C3 inhibition by KV-37 sensitizes ENZ-resistant prostate cancer cells to the chemotherapeutic, and is superior to INDO."

"In conclusion, we highlight the potential of KV-37 as a combination therapy with ENZ for CRPC because it retards ENZ-resistant prostate cancer cell growth and induces apoptosis. Furthermore, it is conceivable from the results of this study that the structurally novel AKR1C3 inhibitor KV-37 scaffold can be developed as a stand-alone therapeutic for prostate cancer management."

[kaptank in reply to JLS1]

thanks. Yes, it's something to keep an eye on.