Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs

Vezmar, Marko; Georges, Elias

doi:10.1016/s0006-2952(00)00270-7

Cited by 76 publications

(44 citation statements)

References 57 publications

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“…It is important to determine whether activation of this pathway in tumor cells following drug treatment is associated with cell death or survival, since it may provide an opportunity to enhance the selectivity and potency of a given therapeutic. Indeed, chloroquine has been reported to increase the activities of doxorubicin, cyclophosphamide, and inhibitors of Akt in certain types of cancer (47)(48)(49). This notion is particularly intriguing when applied to myeloma, a malignancy characterized by progressive chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Targeting Glucose Consumption and Autophagy in Myeloma with the Novel Nucleoside Analogue 8-Aminoadenosine

Shanmugam

McBrayer

Qian

et al. 2009

Journal of Biological Chemistry

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Multiple myeloma, an incurable plasma cell malignancy, is characterized by altered cellular metabolism and resistance to apoptosis. Recent connections between glucose metabolism and resistance to apoptosis provide a compelling rationale for targeting metabolic changes in cancer. In this study, we have examined the ability of the purine analogue 8-aminoadenosine to acutely reduce glucose consumption by regulating localization and expression of key glucose transporters. Myeloma cells counteracted the metabolic stress by activating autophagy. Co-treatment with inhibitors of autophagy results in marked enhancement of cell death. Glucose consumption by drug-resistant myeloma cells was unaffected by 8-aminoadenosine, and accordingly, no activation of autophagy was observed. However, these cells can be sensitized to 8-aminoadenosine under glucose-limiting conditions. The prosurvival autophagic response of myeloma to nutrient deprivation or to nucleoside analogue treatment has not been described previously. This study establishes the potential of metabolic targeting as a broader means to kill and sensitize myeloma and identifies a compound that can achieve this goal. Multiple myeloma (MM)2 is a plasma cell malignancy with a yearly incidence of 14,000 in the United States and accounts for 10% of deaths from hematological malignancies (1). Multiple myeloma remains incurable with a median survival of 3-5 years. Current therapeutic options extend longevity, but patients eventually succumb to the disease due to the development of drug resistance (2).Nucleoside analogues are antimetabolites that play a pivotal role in the treatment of a spectrum of hematological malignancies. Our laboratory has extensively characterized the novel purine nucleoside analogues 8-chloroadenosine and congener 8-aminoadenosine (8-NH 2 -Ado) (3-5), which are highly effective in tissue culture models of multiple myeloma as well as a spectrum of other hematological and solid cancers. 8-Chloroadenosine is currently in phase I clinical trial. The general mechanism of action of these antimetabolites involves RNA and/or DNA termination, ATP depletion, and subsequent induction of apoptosis (6), but a comprehensive analysis of their cellular effects has not been reported.In this study, we describe a novel feature in the mechanism of action of purine nucleoside analogue 8-NH 2 -Ado. We find that 8-NH 2 -Ado inhibits glucose consumption that is associated with an activation of autophagy. This ability to reduce glucose consumption is particularly important, given the dependence of many tumor cells on aerobic glycolysis and the ensuing increase in glucose consumption to meet energetic and biosynthetic demands. Normal cells typically rely on oxygen to metabolize glucose via the glycolytic and oxidative phosphorylation pathways to generate ATP. In contrast, many tumor cells demonstrate enhanced glycolysis and lactate production, utilizing the less efficient mode of ATP production even in the presence of oxygen (7). This phenomenon, termed aerobic glycolysis, was ...

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Section: Discussionmentioning

confidence: 99%

Targeting Glucose Consumption and Autophagy in Myeloma with the Novel Nucleoside Analogue 8-Aminoadenosine

Shanmugam

McBrayer

Qian

et al. 2009

Journal of Biological Chemistry

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“…The high level of PGP in intestine and the fact that PGP inhibitors exhibit signi®cant cross-reactivity with other transporters confounds such studies in normal tissues. For example, both verapamil and quinidine have been shown to interact with MRP transporters (Tomonaga et al, 1996;Makhey et al, 1998;Vezmar & Georges, 2000). Recent studies have implicated non-PGP, non-MRP transporters as possible limiting factors for intestinal permeability (Soldner et al, 2000;Jonker et al, 2000) and there is a growing awareness that our understanding of the drug e ux systems present in the intestine is far from complete.…”

Section: Discussionmentioning

confidence: 99%

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

Stephens

O’Neill

Bennett

et al. 2002

British J Pharmacology

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1 Intestinal xenobiotic transporters are a signi®cant barrier to the absorption of many orally administered drugs. P-glycoprotein (PGP) is the best known, but several others, including members of the multidrug resistance-associated protein (MRP) family, are also expressed. De®nitive information on their precise e ect on intestinal drug permeability is scarce due to a lack of speci®c inhibitors and the di culty of studying non-PGP activity in the presence of high PGP expression. 2 We have investigated the in vitro use of intestinal tissues from PGP knockout (mdr1a (7/7)) mice as a tool for dissecting the mechanisms of intestinal drug e ux. The permeability characteristics of digoxin (DIG), paclitaxel (TAX) and etoposide (ETOP) were measured in ileum from mdr1a (7/7) and wild-type (FVB) mice mounted in Ussing chambers. 3 DIG and TAX exhibited marked e ux across FVB tissues (B-A : A-B apparent permeability (P app ) ratio 10 and 17 respectively) which was absent in mdr1a (7/7) tissues, con®rming that PGP is the sole route of intestinal e ux for these compounds. The A-B P app of both compounds was 3 ± 5 fold higher in mdr1a (7/7) than in FVB. 4 Polarized transport of ETOP in FVB tissues was reduced but not abolished in mdr1a (7/7) tissues. Residual ETOP e ux in mdr1a (7/7) tissues was abolished by the MRP inhibitor MK571, indicating involvement of both PGP and MRP. 5 MK571 abolished calcein e ux in mdr1a (7/7) tissues, while quinidine had no parallel e ect in FVB tissues, suggesting involvement of MRP but not PGP. 6 Tissues from mdr1a (7/7) mice provide a novel approach for investigating the in¯uence of PGP ablation on intestinal permeability and for resolving PGP and non-PGP mechanisms that modulate drug permeability.

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“…Indeed, we recently showed a linear correlation between Pgp expression in lymphocytes and the EC 50 of SQV . Of interest, the antimalarial compounds CQ and MQ also interact with Pgp and/or MRP1, and both drugs have been shown to enhance intracellular accumulation of substrates in cell lines that overexpress these transporters (Riffkin et al, 1996;Vezmar and Georges, 1998;Fujita et al, 2000;Vezmar and Georges, 2000).…”

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confidence: 99%

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

Owen

Janneh²,

Hartkoorn³

et al. 2005

J Pharmacol Exp Ther

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Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells.Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a Ͼ3-fold and Ͼ2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo.

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Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs

Cited by 76 publications

References 57 publications

Targeting Glucose Consumption and Autophagy in Myeloma with the Novel Nucleoside Analogue 8-Aminoadenosine

Targeting Glucose Consumption and Autophagy in Myeloma with the Novel Nucleoside Analogue 8-Aminoadenosine

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

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