Can pharmacogenomics improve malaria drug policy?

Roederer, Mary W.; McLeod, HowardLeod; Juliano, Jonathan J.

doi:10.2471/blt.11.087320

Cited by 27 publications

(17 citation statements)

References 41 publications

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“…83 Remarkably, safety and efficacy of AQ-based antimalarial therapy are well established, and pharmacogenetic profiling of an AQ-metabolizing enzyme (cytochrome P450, family 2, subfamily C, polypeptide 8; encoded by CYP2C8) in malaria patients may improve the safe use of this drug. 88,89 Taken together, our data suggest that AQ is a promising candidate for drug repurposing efforts aimed at undermining autophagic-lysosomal function and proliferative control in malignant melanoma cells. Our current research efforts aim at the identification of specific molecular targets involved in AQ-based inactivation of cancer cells, and studies that aim at demonstrating feasibility of AQ-based adjuvant chemotherapeutic intervention in preclinical murine models of human melanoma have been initiated.…”

Section: Discussionmentioning

confidence: 66%

The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death

Qiao¹,

Tao²,

Vega³

et al. 2013

Autophagy

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Pharmacological inhibition of autophagic-lysosomal function has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Repurposing approved and abandoned non-oncological drugs is an alternative approach to the identification and development of anticancer therapeutics, and antimalarials that target autophagic-lysosomal functions have recently attracted considerable attention as candidates for oncological repurposing. Since cumulative research suggests that dependence on autophagy represents a specific vulnerability of malignant melanoma cells, we screened a focused compound library of antimalarials for antimelanoma activity. Here we report for the first time that amodiaquine (AQ), a clinical 4-aminoquinoline antimalarial with unexplored cancer-directed chemotherapeutic potential, causes autophagic-lysosomal and proliferative blockade in melanoma cells that surpasses that of its parent compound chloroquine. Monitoring an established set of protein markers (LAMP1, LC3-II, SQSTM1) and cell ultrastructural changes detected by electron microscopy, we observed that AQ treatment caused autophagic-lysosomal blockade in malignant A375 melanoma cells, a finding substantiated by detection of rapid inactivation of lysosomal cathepsins (CTSB, CTSL, CTSD). AQ-treatment was associated with early induction of energy crisis (ATP depletion) and sensitized melanoma cells to either starvation- or chemotherapeutic agent-induced cell death. AQ displayed potent antiproliferative effects, and gene expression array analysis revealed changes at the mRNA (CDKN1A, E2F1) and protein level (TP53, CDKN1A, CCND1, phospho-RB1 [Ser 780]/[Ser 807/811], E2F1) consistent with the observed proliferative blockade in S-phase. Taken together, our data suggest that the clinical antimalarial AQ is a promising candidate for repurposing efforts that aim at targeting autophagic-lysosomal function and proliferative control in malignant melanoma cells.

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Section: Discussionmentioning

confidence: 66%

The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death

Qiao¹,

Tao²,

Vega³

et al. 2013

Autophagy

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“…In humans, other possible causes of hemolysis include genetic susceptibility such as polymorphisms in drug metabolizing enzymes -CYP2A6 (Roederer et al, 2011), hemoglobinopathies such G-6-P-D deficiency which is common in malaria endemic areas (Beutler et al, 2007;Howes et al, 2012;Price et al, 2001;Van Malderen et al, 2012) and suppressed erythropoiesis after administration of artemisinin, in the presence of other hemolytic factors such as malaria parasite, it would result in anemia as seen in hyperparasitemic individuals.…”

Section: Discussionmentioning

confidence: 99%

Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

et al. 2017

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Background: Hemolysis is common in malaria infection and during the course of treatment. Previous studies have reported delayed post-artemisinin hemolysis occurring in naïve and immune individuals treated with parenteral or oral artemisinin-derivatives. This study aims to understand if delayed hemolysis occurs in the absence of malaria parasites and the underlying mechanisms for the hemolytic effects after administration of two antimalarial drugs to malaria-free Wistar rats. Methods: Forty animals were randomized into 5 groups of eight animals each; they received 4 mg/kg artesunate for 7 days (AS), 4 mg/kg artesunate plus 10mg/kg amodiaquine for 3 days (ASQ), 10mg/kg amodiaquine for 3 days (AQ), distilled water [normal control], (Control) and 1mg/kg phenylhydrazine for 1 day to induce hemolysis (PHZ) groups respectively. Packed cell volume (PCV), white blood cell differential count and serum haptoglobin (Hpt) levels were determined in all groups on day 4 and 18 to detect hemolysis. Mean values were compared using t-test and ANOVA with p values <0.05 taken to be significantly different. Results: Post-treatment mean PCV on day 4 was significantly lower than day 18 in all groups except AS group which had similar PCV all through evaluation. Although AQ had lowest mean PCV on day 4, by day 18, mean PCV returned to normal and hpt levels was significantly higher than AS and ASQ groups (p<0.001). Hpt level (mean ± sem) for AS, ASQ, AQ, and control on day 18 were: 18.67 ± 0.004, 50.66 ± 0.014, 73.06 ± 0.003, and 74.13 ± 0.032 mg/dl respectively (p < 0.0001). On day 18, AS and ASQ had significantly lower Hpt level compared to day 4 (p <0.001). No neutropenia was observed during the study. Conclusion: Artesunate induces delayed hemolysis in malaria-free animals possibly through an oxidative toxic effect on the red blood cell membrane. Delayed post-treatment hemolysis was not observed with artesunateamodiaquine or amodiaquine alone.

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“…CYP2A6 plays a major role in metabolizing artesunate to its active anabolite, dihydroartemisinin [16,17], while CYP2B6, CYP1A1 and CYP1A2 play minor roles [19]. Compared to the reference CYP2A6*1A allele, approximately 40 gene variants exist, of which at least 13 demonstrate decreased metabolism and three no activity in vivo (selected genotypes are listed in Table 3) [191,192].…”

Section: Antimalarial Agentsmentioning

confidence: 99%

Pharmacogenomics of Antimicrobial Agents

et al. 2014

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Antimicrobial efficacy and toxicity varies between individuals owing to multiple factors. Genetic variants that affect drug-metabolizing enzymes may influence antimicrobial pharmacokinetics and pharmacodynamics, thereby determining efficacy and/or toxicity. In addition, many severe immune-mediated reactions have been associated with HLA class I and class II genes. In the last two decades, understanding of pharmacogenomic factors that influence antimicrobial efficacy and toxicity has rapidly evolved, leading to translational success such as the routine use of HLA-B*57:01 screening to prevent abacavir hypersensitivity reactions. This article examines recent advances in the field of antimicrobial pharmacogenomics that potentially affect treatment efficacy and toxicity, and challenges that exist between pharmacogenomic discovery and translation into clinical use.

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Can pharmacogenomics improve malaria drug policy?

Cited by 27 publications

References 41 publications

The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death

The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death

Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

Pharmacogenomics of Antimicrobial Agents

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