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...
Anyone prescribe Metformin for prostate cancer not for diabetes? 
Oncolytic Virus Therapy for Pca
Aspirin, metformin and propranolol
