Spironolactone and XPB: An Old Drug with a New Molecular Target

Abstract

Spironolactone (SP) is commonly used for the treatment of heart failure, hypertension, and complications of cirrhosis by antagonizing the mineralocorticoid receptor. However, SP also antagonizes the androgen receptor, and thus SP has also been shown to be effective in the treatment of acne, hair loss, and hirsutism in women. Interestingly, recent drug repurposing screens have identified new and diverse functions for SP as a simulator of tumor immunosurveillance and as an inhibitor of DNA repair and viral infection. These novel pharmacological effects of SP have all been linked to the ability of SP to induce the rapid proteolytic degradation of the xeroderma pigmentosum group B (XPB) protein. XPB is a critical enzymatic component of the multi-subunit complex known as transcription factor II-H (TFIIH), which plays essential roles in both DNA repair and the initiation of transcription. Given the critical functions for XPB and TFIIH in these processes, the loss of XPB by SP could lead to mutagenesis. However, the ability of SP to promote cancer stem cell death and facilitate immune recognition may counteract the negative consequences of SP to mitigate carcinogenic risk. Thus, SP appears to have new and interesting pharmacological effects that may extend its potential uses.

Spironolactone-induced XPB degradation requires TFIIH integrity and ubiquitin-selective segregase VCP/p97

“…Mutant XPB containing serine to alanine mutation at amino acid 90 was resistant to spironolactoneinduced XPB degradation. XPB phosphorylation is proposed to facilitate spironolactone-induced XPB degradation [43]. Yet, how Cdk7 within CAK contributes to spironolactone-induced XPB degradation remains largely unclear.…”

Novel Insights into the Role of the Mineralocorticoid Receptor in Human Glioblastoma

“…Interestingly, SPI’s pro-proliferative effects seen in established GBM cells were no longer observed when their capacity to form stem cell enriched neurospheres was assessed. SPI blocked the self-renewal of GSCs, an effect previously observed in carcinoma stem cells [ 24 ]. Furthermore, while DEXA led to increased GSC sphere formation, SPI significantly blocked this activity.…”

The role of aldosterone inhibitors in cardiac ischemia–reperfusion injury

“…Due to the MR antagonism in the kidney, spironolactone results in increased excretion of sodium and water to lower fluid retention and lessen pressure on the heart (Gabbard et al 2020). Spironolactone was first approved as a diuretic drug for the management of hypertension and primary aldosteronism, and later for edematous conditions in patients diagnosed with congestive heart failure.…”