Diazoxide for Lowering Insulin Levels in Breast Cancer Patients

Abstract

Diazoxide is a nondiuretic benzothiadiazine that produces hyperglycemia by lowering insulin levels through activation of ATP‐sensitive K1‐channels and stimulating insulin degradation in the lysosomal system. Its effect on cancer growth is discussed.

Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity**

“…In this reported study, as observed herein, the activity of DZX was highly dependent on the cell line employed; no activity was observed in MCF‐7 breast cancer cells (IC 50 =130 μM) but in MDA‐MB‐468 TNBC cells an IC 50 =0.87 μM was reported for DZX [37] . The potential of repurposing DZX in breast cancer has been advanced previously, with the authors suggesting combination treatment to manage the hyperglycemia “side effect” of DZX in this context [50] . Our studies dispute the use of DZX for direct repurposing as in our hands, DZX is inactive in MDA‐MB‐468 TNBC cells as well as in a prostate cancer cell line.…”

“…37 The potential of repurposing DZX in breast cancer has been advanced previously, with the authors suggesting combination treatment to manage the hyperglycemia 'side effect' of diazoxide in this context. 50 Our studies dispute the use of DZX for direct repurposing as in our hands, DZX is inactive in MDA-MB-468 TNBC cells as well as in a prostate cancer cell line. Through the SAR studies initiated herein, medicinal chemistry modulation of the parent compound has been shown to increase antineoplastic effect significantly and presents the possibility of tuning out the known pharmacophore of KATP opening activity along with the associated hyperglycemic effect, potentially allowing access to novel treatments for cancer.…”

“…Diazoxide has been investigated in one pilot clinical study in breast cancer patients at a dose of 200–300 mg/day. Treatment of nine patients resulted in a 33 % response rate conferring stable disease for between 4–8 months either in combination with tamoxifen (two patients) or monotherapy (one patient) [50] . The repurposing of DZX as a potential treatment for TNBC has been recently proposed based on a study employing a KinomeScan TM assay of 438 kinases, the three most inhibited kinases at 100 μM were TTK (15 %), IRAK1 (9 %) and DYRK1 A (7 %).…”

Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity

“…37 The potential of repurposing DZX in breast cancer has been advanced previously, with the authors suggesting combination treatment to manage the hyperglycemia 'side effect' of diazoxide in this context. 50 Our studies dispute the use of DZX for direct repurposing as in our hands, DZX is inactive in MDA-MB-468 TNBC cells as well as in a prostate cancer cell line. Through the SAR studies initiated herein, medicinal chemistry modulation of the parent compound has been shown to increase antineoplastic effect significantly and presents the possibility of tuning out the known pharmacophore of KATP opening activity along with the associated hyperglycemic effect, potentially allowing access to novel treatments for cancer.…”

“…Treatment of nine patients resulted in a 33% response rate conferring stable disease for between 4-8 months either in combination with tamoxifen (two patients) or monotherapy (one patient). 50 The repurposing of DZX as a potential treatment for TNBC has been recently proposed based on a study employing a KinomeScan TM assay of 438 kinases, the three most inhibited at 100 µM were TTK (15%), IRAK1 (9%) and DYRK1A (7%). Dysfunction of all three kinases are known to be associated with various cancers.…”