Reduced Digestive Vacuolar Accumulation of Chloroquine Is Not Linked to Resistance to Chloroquine Toxicity

Chloroquine (CQ) accumulation studies in live malaria parasites are typically conducted at low nanomolar CQ concentrations, and definition of CQ resistance (CQR) has been via growth inhibition assays versus low-dose CQ (i.e., via IC(50) ratios). These data have led to the nearly universally accepted idea that reduced parasite CQ accumulation is the underlying basis of CQR. Surprisingly, when quantifying CQR via cytocidal CQ activity and examining CQ accumulation at medically relevant LD(50) doses, we find reduced CQ accumulation is not the underlying cause of CQR.