Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies.
Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies.
Cancer Center Karolinska; Department of Oncology-Pathology; Karolinska Institute; Stockholm, Sweden.
Paola
P
Pellegrini
Cancer Center Karolinska; Department of Oncology-Pathology; Karolinska Institute; Stockholm, Sweden.
Angela
A
Strambi
Cancer Center Karolinska; Department of Oncology-Pathology; Karolinska Institute; Stockholm, Sweden.
Chiara
C
Zipoli
Cancer Center Karolinska; Department of Oncology-Pathology; Karolinska Institute; Stockholm, Sweden.
Maria
M
Hägg-Olofsson
Cancer Center Karolinska; Department of Oncology-Pathology; Karolinska Institute; Stockholm, Sweden.
Maria
M
Buoncervello
Cancer Center Karolinska; Department of Oncology-Pathology; Karolinska Institute; Stockholm, Sweden.
Stig
S
Linder
Cancer Center Karolinska; Department of Oncology-Pathology; Karolinska Institute; Stockholm, Sweden.
Angelo
A
De Milito
D000143:Acids; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009369:Neoplasms / Q000188:drug therapy*; D059016:Tumor Microenvironment / Q000502:physiology*
D000143:Acids; D002738:Chloroquine
autophagy; cancer therapy; chloroquine; pH; tumor acidosis