Abstract
Background: Previous studies of patients with acute leukemia showed that plasma cGMP levels were markedly elevated before treatment, fell after successful therapy but increased after relapse. In many cells high concentrations of GMP have an antiproliferative effect. The cellular cGMP extrusion from cancer cells may represent an acquired resistance against an endogenous antiproliferative signal molecule. Multidrug resistance associated protein 5 (MRP5) has been identified as an important cGMP transporter. Methods: A human erythroleukemia cell line (HEL) was used to study the impact of cGMP and cGMP-elevating compounds like theophylline, sodium nitroprusside (SNP) and sodium nitrite (NaNO2). MRP5 was overexpressed in HEL cells by transfection. Concentrations of cGMP were determined with RIA or HPLC and cell densities were determined by cytometry. Results: The concentration ratio between extra- and intracellular cGMP concentrations was >1, meaning that HEL cells extruded cGMP against a concentration gradient and MRP5 was identified in these cells. In some cell types butyrate increases cellular cGMP levels by stimulating soluble guanylyl cyclase (sGC) and thereby the cellular efflux. This effect did not exist for HEL cells. MRP5 transfected HEL cells which were exposed to cGMP was clearly more sensitive to the antiproliferative effect than the wild type. On the other hand, exposing the transfected HEL cells to cGMP-elevating agents (theophylline, SNP and NaNO2) showed less sensitivity than the wildtype. Conclusion: This study supports the idea that some cancers acquire resistance against endogenous signal molecules with antiproliferative potency.
Highlights
The observation that some cancer types were associated with increased extracellular cGMP levels during active disease forwarded the idea of an acquired resistance against an endogenous molecule with antiproliferative properties
Butyrate concentrations up to 100 μM had minimal effect on human erythroleukemia cell line (HEL) cell growth compared to baseline
The effect of butyrate on intra- and extracellular cGMP levels were determined below growth-modulating concentrations
Summary
The observation that some cancer types were associated with increased extracellular cGMP levels during active disease forwarded the idea of an acquired resistance against an endogenous molecule with antiproliferative properties. This phenomenon has been well documented for leukemia and some gynecologic cancers. Urine cGMP levels were significantly higher in those patients with poorly differentiated tumors Serial measurements made it possible to predict relapse in 64% prior to other clinical signs. Previous studies of patients with acute leukemia showed that plasma cGMP levels were markedly elevated before treatment, fell after successful therapy but increased after relapse. Conclusion: This study supports the idea that some cancers acquire resistance against endogenous signal molecules with antiproliferative potency
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