Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

Abstract

Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 μM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl− and the decreased HCO3− concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na–K–2Cl electroneutral cotransporter or Cl−/HCO3− anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells.

Pimarane diterpenes: Natural source, stereochemical configuration, and biological activity

“…88 It was much less sensitive against leukemia cell lines (32% or less). 88 It was much less sensitive against leukemia cell lines (32% or less).…”

A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

“…One cation-chloride cotransporter that has eluded the list of cotransporters with human mutations is the ubiquitous Na-K-2Cl cotransporter-1 or NKCC1. NKCC1, like its family of transporters, plays a role in epithelial ion transport (O'Mahony et al 2008; Bouyer et al 2013; Kidokoro et al 2014; Wei et al 2015), modulates inhibitory synaptic transmission (Sung et al 2000; Dzhala et al 2005), and maintains and regulates cell volume (Wu et al 1998; Bush et al 2010; Mathieu et al 2015). Accordingly, the knockout mouse exhibits multiple phenotypes that include sensorineural deafness (Delpire et al 1999; Dixon et al 1999; Flagella et al 1999), male infertility (Pace et al 2000), intestinal transit deficiency (Flagella et al 1999; Wouters et al 2006; Bradford et al 2016), deficit in saliva secretion (Evans et al 2000), and a pain perception phenotype (Sung et al 2000; Laird et al 2004; Granados-Soto et al 2005).…”

Isatin derivatives with activity against apoptosis-resistant cancer cells

“…7–10 Our recent studies have focused on the class on natural products known as indirubins (Figure 1A). 11 The 2,3`-bis-indoles have been reported to modulate glycogen synthase kinase (GSK)-3, 11,12 5-lipoxygenase (5-LO), 13 tyrosine kinases, 14 and aryl hydrocarbon (Ah) receptor.…”