Long before Ozempic and Mounjaro, there were mitochondrial uncouplers. While deadly if not used with care, it might be time for them to make a comeback.
Okay, that’s a stupid question as the answer is “read the link” but having read the link I’m pretty unconvinced about cancer applications in particular
I think you're right to be skeptical until we see evidence from later stage trials! However, I recommend this paper "We need to talk about the Warburg effect" (https://www.nature.com/articles/s42255-020-0172-2), it covers some of the misconceptions about the 'glycolytic switch' -- namely that many tumours do make significant use of mitochondrial metabolism. From the review: "In short, genetically defined impairments in oxidative metabolism may stimulate aerobic glycolysis in cancer, but, in general, aerobic glycolysis does not predict loss of oxidative metabolism."
The rationale for uncouplers then is analogous to the rationale for chemotherapy: cancer cells are more susceptible to certain kinds of stress (e.g. DNA replication, metabolic stress) than normal cells and this can be exploited.
Yeah I think I’d be less skeptical if we didn’t already have 50+ years of drug development along the lines of “cancer cells are generally more susceptible to poison lets do poison”. That strategy works, it’s amazing/lifesaving that we have that strategy, but I don’t know there’s that much more juice to be squeezed out of it
I.e. there is a “better than the Beatles” problem for a putative uncoupler therapy where it has to outperform antifolates topoisomerase inhibitors cisplatin microtubule inhibitors etc etc, such that an uncoupler would work in a world where those didn’t exist but might not add value today
Excellent article and discussion/description of the electron transport chain and mitochondrial uncouplers. Thanks Alex.
Why would uncouplers be good against cancer? Don’t cancer cells predominantly use anaerobic metabolism anyway?
Okay, that’s a stupid question as the answer is “read the link” but having read the link I’m pretty unconvinced about cancer applications in particular
I think you're right to be skeptical until we see evidence from later stage trials! However, I recommend this paper "We need to talk about the Warburg effect" (https://www.nature.com/articles/s42255-020-0172-2), it covers some of the misconceptions about the 'glycolytic switch' -- namely that many tumours do make significant use of mitochondrial metabolism. From the review: "In short, genetically defined impairments in oxidative metabolism may stimulate aerobic glycolysis in cancer, but, in general, aerobic glycolysis does not predict loss of oxidative metabolism."
The rationale for uncouplers then is analogous to the rationale for chemotherapy: cancer cells are more susceptible to certain kinds of stress (e.g. DNA replication, metabolic stress) than normal cells and this can be exploited.
Yeah I think I’d be less skeptical if we didn’t already have 50+ years of drug development along the lines of “cancer cells are generally more susceptible to poison lets do poison”. That strategy works, it’s amazing/lifesaving that we have that strategy, but I don’t know there’s that much more juice to be squeezed out of it
I.e. there is a “better than the Beatles” problem for a putative uncoupler therapy where it has to outperform antifolates topoisomerase inhibitors cisplatin microtubule inhibitors etc etc, such that an uncoupler would work in a world where those didn’t exist but might not add value today