Deguelin for PTEN-deficient PCa. & a... - Advanced Prostate...

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Deguelin for PTEN-deficient PCa. & an aside on Metformin.

pjoshea13 profile image
10 Replies

New study below [1]. Perhaps not an easy read - so, apologies in advance.

Deguelin is a "naturally occurring insecticide" [2].

PTEN is a tumor suppressor gene that may be silenced in PCa [3].

"Highly selective killing of Pten-null cells can be achieved by deguelin, a natural insecticide. Deguelin eliminates Pten-deficient cells through inhibition of mitochondrial complex I (CI). Five hundred-fold higher drug doses are needed to obtain the same killing of Pten-WT cells, even though deguelin blocks their electron transport chain equally well."

In other words, you would need 500 times the amount of insecticide to kill normal cells with functional (wild-type [WT]) PTEN.

"Selectivity arises because mitochondria of Pten-null cells consume ATP through complex V, instead of producing it. The resulting glucose dependency can be exploited to selectively kill Pten-null cells with clinically relevant CI inhibitors, especially if they are lipophilic."

...

"Landmark studies have connected metformin use with reduced cancer mortality (Landman et al., 2010, Xu et al., 2015), spawning a number of clinical trials (as reviewed in Pernicova and Korbonits, 2014). In prostate specifically, a decrease in cancer mortality has been seen, but not in cancer incidence (Margel et al., 2013a, Margel et al., 2013b). This suggests that metformin may preferentially target aggressive PC, which is the subject of ongoing trials (Gillessen et al., 2016). The discovery of CI as the functional target of metformin (Wheaton et al., 2014) has led to development of trials with more effective yet tolerated drugs, such as the IACS-010759 compound used in this study."

"Our results can contribute to these efforts. They point to a mitochondrial vulnerability, driven by complex V inversion, for achieving highly selective killing of advanced Pten-deficient PC cells. They suggest that maximal selective killing by a given CI inhibitor is dependent on two completely intertwined factors: (1) depletion of tumor cell glucose supplies and (2) the inhibitor’s properties of transport to the target. The first point should be critical in trial design: currently CI inhibitors such as metformin are given to PC patients with or just after meals (i.e., coinciding with highest plasma glucose levels), following the paradigm established for diabetes. Our results instead suggest that greater selectivity might be achieved if drugs are given when blood glucose levels are low. The second point should be critical for drug design: we found that changes in CI inhibitor properties critically affect the optimal time to achieve genotype-selective killing. This effect was most striking when comparing deguelin with rotenone (Figure 3C). Therefore, drug optimization could benefit from the type of time and genotype-selective approach on which our study is based."

-Patrick

[1] FULL Text:

cell.com/cell-reports/fullt...

[2] en.wikipedia.org/wiki/Deguelin

[3] en.wikipedia.org/wiki/PTEN_...

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pjoshea13
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10 Replies
tango65 profile image
tango65

Very interesting.

hadleycash profile image
hadleycash

Would like to hear the follow up on Deguelin from your oncologist visit. Keep us posted. I'm BRCA-2 and P53 mutation positive also, but don't know about PTEN.

Mazdaguy profile image
Mazdaguy

I’ve been thinking about this. A lot of us take Metformin for it’s possible PC benefit. Given what they’re saying I wonder if taking Metformin would be more beneficial if we took it when blood Glucose is at its lowest vs. how most of us take it now—-at a meal.

paige20180 profile image
paige20180

Thanks for the article. Does anyone have an idea how much Metformin?

pjoshea13 profile image
pjoshea13 in reply to paige20180

I use 2,000 mg (divided dose) daily, because of a Swiss PCa study. Dr. Myers was influenced by that study too.

Prior to that I was on 1,000 mg for years.

You have to start slowly with Metformin. One 500 mg tablet for a couple of weeks before adding another. This can avoid the gastro upset that some experience.

-Patrick

CantChoose profile image
CantChoose

One interesting thing I've noticed is my husband's glucose creeping up as his PSA drops. His labs yesterday had him at 200! That's not a fasting level and it was right after lunch, but still, that's quite high for a non-diabetic. I keep asking him to ask his MO but they seem unconcerned.

Wonder if changes in glucose metabolism are part of the mutation process somehow. I know PC supposedly likes a high sugar environment, but wondering if somehow the cancer directly affects it.

pjoshea13 profile image
pjoshea13 in reply to CantChoose

Unfortunately, loss of testosterone has a bad effect on symptoms of the metabolic syndrome. It tends to create a pre-diabetic state. Exercise can help.

PCa may be unique in not immediately switching to glycolysis. PCa cells continue to frefer fatty acids for energy. However, the switch can occur in more advanced states.

One way to reduce post-prandial glucose is to make sure there is sufficient fat in the meal. The Mediterranean diet is 40% fat.

The carb:fat:protein ratio in Barry Sears ZONE diet is a good guide IMO.

The high glucose may not be a direct threat, but the insulin response is, IMO. When one loses insulin sensitivity due to frequent glucose challenges, the pancreas starts producing higher levels.

Metformin would help control the sugar high.

-Patrick

CantChoose profile image
CantChoose in reply to pjoshea13

Wow, great info, thank you. Been wondering why they haven't put him on metformin. Maybe he should ask his regular doc.

paige20180 profile image
paige20180

I don’t know what we would do without you guys❤️

CantChoose profile image
CantChoose in reply to paige20180

I think that a lot. This board is like no other.

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