Impact of Extracellular Acidity on the Activity of P-glycoprotein and the Cytotoxicity of Chemotherapeutic Drugs

Abstract

The expression and activity of P-glycoprotein (pGP) play a role in the multidrug resistance of tumors. Because solid-growing tumors often show pronounced hypoxia or extracellular acidosis, this study attempted to analyze the impact of an acidic environment on the expression and activity of pGP and on the cytotoxicity of chemotherapeutic agents. For this, prostate carcinoma cells were exposed to an acidic extracellular environment (pH 6.6) for up to 24 hours. pGP activity was more than doubled after 3 to 6 hours of incubation in acidic medium, whereas cellular pGP expression remained constant, indicating that increased transport rate is the result of functional modulation. In parallel, the cytotoxic efficacy of daunorubicin showed pronounced reduction at low pH, an effect that was reversible on coincubation with a pGP inhibitor. A reduction of intracellular Ca2+ concentration by 35% under acidic conditions induced a higher transport rate of pGP, an effect comparable to that found on inhibition of protein kinase C (PKC). These data indicate that pGP activity is increased by low extracellular pH presumably as a result of lowered intracellular calcium levels and inhibition of PKC. These findings may explain the reduced cytotoxicity of chemotherapeutic agents in hypoxic/acidic tumors.

Investigating Effects of Acidic pH on Proliferation, Invasion and Drug-Induced Apoptosis in Lymphoblastic Leukemia

“…Raghunand et al (1999) reported that the extracellular pH of human breast tumor is acidic, which reduces the cytotoxicity of doxorubicin [17]. Thews et al (2006) showed that acidic extracellular microenvironment can induce activity of p-glycoprotein which leads to reduce the concentration and cytotoxicity of chemotherapeutic drug by pumping entered drug to outside [41]. Lan et al (2007) demonstrated microenvironmental pH can control the type of cell death.…”

The acidic microenvironment as a possible niche of dormant tumor cells

“…Among these, it is of a great importance the ability of acidic pH e to increase the pump activity of the p-glycoprotein (pGP), a drug efflux transporter. Thews et al observed that acidic prostate carcinoma cells express a pGP activity more than doubled of that of cells grown in a standard pH medium [107]. These authors reported that up-regulation of pGP in acidic cells was related to an increased intracellular Ca 2+ level, stimulated by a protein kinase C activity [107].…”

“…Thews et al observed that acidic prostate carcinoma cells express a pGP activity more than doubled of that of cells grown in a standard pH medium [107]. These authors reported that up-regulation of pGP in acidic cells was related to an increased intracellular Ca 2+ level, stimulated by a protein kinase C activity [107]. It has also been observed that acidosis-induced pGP activity may be related to ERK and p38 pathways.…”

Acidosis Promotes Bcl-2 Family-mediated Evasion of Apoptosis

“…Stresses-Abundant evidence confirms that extracellular acidity has a positive effect on the survival and malignant potential of many cancer cells (5,6,31). Although more intensively studied in solid tumors, acidosis is known to occur in the microenvironment of hematologic malignancies as well (3).…”