naphthoquinones and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

The use of trimethoprim/sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia in patients with acute lymphoblastic leukemia (ALL) may cause undesirable adverse effects: fungal overgrowth, neutropenia, and drug resistance. A possible alternative is atovaquone, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity. However, it is not known if atovaquone alters the disposition or adverse effects of antileukemic drugs.. Using a crossover study design, we compared the pharmacokinetics of etoposide and its CYP3A4-formed catechol metabolite when given as a 300 mg/m2 i.v. infusion following daily atovaquone versus trimethoprim/sulfamethoxazole in nine patients.. The area under the concentration time curve (AUC) of etoposide, etoposide catechol and the catechol to etoposide AUC ratio were slightly higher (a median of 8.6%, 28.4%, and 25.9%) following atovaquone as compared to trimethoprim/sulfamethoxazole (P=0.055, P= 0.031 and P=0.023), respectively. In vitro analysis in human liver microsomes showed modest inhibition of etoposide catechol formation in the presence of atovaquone. Using uptake of 3H-vinblastine in L-MDR1 cells, atovaquone was shown to inhibit P-glycoprotein with an apparent Ki of 95.6 microM.. Although the effect of atovaquone on etoposide disposition was modest, in light of the fact that the risk of etoposide-related secondary acute myeloid leukemia has been linked to minor changes in schedule and concurrent therapy, we suggest caution with the simultaneous administration of atovaquone and etoposide, particularly if used with other CYP3A4/P-glycoprotein substrates.

Topics: Adolescent; Antifungal Agents; Antineoplastic Agents, Phytogenic; Area Under Curve; Atovaquone; Child; Child, Preschool; Cross-Over Studies; Drug Interactions; Etoposide; Female; Humans; Lymphoma, Non-Hodgkin; Male; Naphthoquinones; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Trimethoprim, Sulfamethoxazole Drug Combination

Multidrug resistance (MDR) represents a serious problem in cancer treatment. One strategy to overcome this obstacle is to identify agents that are selectively lethal to MDR cells. The aim of this study was to discover novel compounds against MDR leukemia and to determine the molecular mechanisms behind collateral sensitivity. A library of 1162 compounds was tested against parental, drug-sensitive CCRF-CEM cells using the resazurin assay. A total of 302 compounds showed reasonable activity (less than 50% cell viability). Eleven out of 30 lawsone derivatives revealed considerable collateral sensitivity in MDR P-glycoprotein (Pgp)-overexpressing CEM/ADR5000 cells. They reduced β-catenin activity in a Wnt/β-catenin reporter cell line. Their activities significantly correlated with apolar desolvation (R = 0.819). Compound (1) (3-hydroxy-1,4-dioxo-N-phenyl-naphthalene-2-carboxamide) was the most active compound and dose-dependently down-regulated protein expression of β-catenin, c-MYC, Pgp and Frizzled 7. By molecular docking, we predicted that compound (1) bound to the palmitoyl-binding groove of the cysteine-rich domain of Frizzled-7 and Frizzled-8. Compound (1) neither stimulated ATPase activity of Pgp nor reactive oxygen species generation, both of which have been previously described as possible mechanisms of collateral sensitivity. Instead, we found that Wnt/β-catenin signaling was selectively inhibited in CEM/ADR5000 cells, but not in CCRF-CEM cells. In conclusion, we found for the first time that the inhibition of Wnt/β-catenin signaling may represent a novel molecular mechanism of collateral sensitivity in MDR cells. Wnt/β-catenin signaling, therefore, represents a potential therapeutic target for the selective killing of Pgp-mediated MDR.

Topics: Antineoplastic Agents; beta Catenin; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Molecular Structure; Naphthoquinones; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reactive Oxygen Species; Signal Transduction; Wnt Proteins

Novel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and role of YM155 for therapeutic use in the context of ALL.. Primary ALL samples and ALL cell lines were interrogated with YM155 to identify drug sensitivity. Ph(+)ALL harboring the BCR-ABL1 oncogene were tested for any interaction with YM155 and the multi-kinase inhibitor dasatinib. Representative ALL cell lines were tested to identify the response to YM155 using standard biochemical assays as well as RNA expression and phosphorylation arrays.. ALL samples exhibited significant sensitivity to YM155, and an additive response was observed with dasatinib in the setting of Ph(+)ALL. ALL cells were more sensitive to YM155 during S phase during DNA replication. YM155 activates the DNA damage pathway leading to phosphorylation of Chk2 and H2AX. Interestingly, screening of primary patient samples identified unique and exquisite YM155 sensitivity in some but not all ALL specimens.. These results are the first to have screened a large number of primary patient leukemic samples to identify individual variations of response to YM155. Our studies further support that YM155 in ALL induces DNA damage leading to S phase arrest. Finally, only subsets of ALL have exquisite sensitivity to YM155 presumably through both suppression of survivin expression and activation of the DNA damage pathway underscoring its potential for therapeutic development.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cells, Cultured; Comet Assay; DNA Damage; Dose-Response Relationship, Drug; Humans; Imidazoles; Immunoblotting; Inhibitory Concentration 50; Naphthoquinones; Precursor Cell Lymphoblastic Leukemia-Lymphoma