- Reaction score
- 320
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834294/
Previous work from our laboratory and others demonstrated that CaP cells use both primary and secondary backdoor pathways to synthesize DHT [5, 8–10]. The terminal step in the primary backdoor pathway is the conversion of DIOL to DHT [5, 10, 11] by any of the four 3α-oxidoreductases: [1] 17β-hydroxysteroid dehydrogenase (HSD) 6 (HSD17B6); [2] retinol dehydrogenase (RDH) 16 (RDH16); [3] dehydrogenase/reductase family member 9 (DHRS9, formerly RDH15); and [4] dehydrogenase/reductase family member 5 (RDH5) [5, 11–13]. The secondary backdoor pathway involves the conversion of DHEA to ASD by HSD3B1 or HSD3B2. ASD is converted subsequently to 5α-dione by SRD5A1 and 5α-dione is converted to DHT by AKR1C3 or HSD17B3
Androgen metabolism inhibitors, such as the SRD5A inhibitor, dutasteride, or the CYP17A1 inhibitor, abiraterone [7, 17], have been disappointing clinically
CaP resistance to abiraterone presumably resulted from enzyme redundancy, progesterone accumulation that led to increased CYP17A1 expression and/or the generation of AR splice variants
Inhibition of the terminal steps of the frontdoor pathway using dutasteride and the primary backdoor pathway using 3α-oxidoreductase catalytic mutants lowered DHT more effectively than either alone.
Previous work from our laboratory and others demonstrated that CaP cells use both primary and secondary backdoor pathways to synthesize DHT [5, 8–10]. The terminal step in the primary backdoor pathway is the conversion of DIOL to DHT [5, 10, 11] by any of the four 3α-oxidoreductases: [1] 17β-hydroxysteroid dehydrogenase (HSD) 6 (HSD17B6); [2] retinol dehydrogenase (RDH) 16 (RDH16); [3] dehydrogenase/reductase family member 9 (DHRS9, formerly RDH15); and [4] dehydrogenase/reductase family member 5 (RDH5) [5, 11–13]. The secondary backdoor pathway involves the conversion of DHEA to ASD by HSD3B1 or HSD3B2. ASD is converted subsequently to 5α-dione by SRD5A1 and 5α-dione is converted to DHT by AKR1C3 or HSD17B3
Androgen metabolism inhibitors, such as the SRD5A inhibitor, dutasteride, or the CYP17A1 inhibitor, abiraterone [7, 17], have been disappointing clinically
CaP resistance to abiraterone presumably resulted from enzyme redundancy, progesterone accumulation that led to increased CYP17A1 expression and/or the generation of AR splice variants
Inhibition of the terminal steps of the frontdoor pathway using dutasteride and the primary backdoor pathway using 3α-oxidoreductase catalytic mutants lowered DHT more effectively than either alone.