The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines

Medeiros, Bruno C.; Landau, H J; Morrow, Mark; Lockerbie, R O; Pitts, Todd M.; Eckhardt, S. Gail

doi:10.1038/sj.leu.2404539

Cited by 30 publications

(27 citation statements)

References 24 publications

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“…In some clinical trials, treatment with FTIs alone or in combination with chemotherapeutic agents failed to improve the overall outcome of patients with solid tumors and leukemia [494,495,496,497,498,499,500,501]. However, other clinical trials demonstrated that the combination of FTIs with conventional chemotherapeutic agents might be useful in hematologic and some solid tumors [502,503,504,505,506,507,508]. Moreover, patients with poor-risk acute myeloid leukemia may benefit from FTIs maintenance therapy following cytotoxic induction and consolidation therapies [509].…”

Section: Targeting Chromosome Congression For Cancer Therapymentioning

confidence: 99%

Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

174

176

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Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed.

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Section: Targeting Chromosome Congression For Cancer Therapymentioning

confidence: 99%

Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

174

176

View full text Add to dashboard Cite

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“…For example, multiple novel, targeted, anticancer agents have been shown to have inhibitory properties against P-gp and other MDR protein activities, through direct inhibition, through activities as competitive A number of farnesyltransferase and tyrosine kinase inhibitors have demonstrated the ability to reverse MDR. Tipifarnib significantly inhibited daunorubicin efflux in leukemia cell lines overexpressing P-gp and showed synergistic proliferation inhibition and apoptosis induction (Medeiros et al, 2007), whereas lapatinib, erlotinib, and nilotinib were shown to inhibit the efflux activity of P-gp and BCRP by functioning as substrates for those transporters (Shi et al, 2007Dai et al, 2008;Dohse et al, 2010). Nintedanib, an inhibitor of vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptor tyrosine kinases, inhibited P-gp activity in P-gp-overexpressing cancer cells and enhanced doxorubicin and paclitaxel cytotoxicity .…”

Section: Downloaded Frommentioning

confidence: 99%

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

Xia

Smith

2012

Mol Pharmacol

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“…3 In addition, it is well known that P-gp overexpression confers resistance to a wide range of caspase-dependent proapoptotic agents, not only by removing drugs from the cells, but also by inhibiting the activation of caspases, a family of proteases, which are key players in apoptotic cell death. 4 Only a few drugs are reported to overcome the MDR phenotype induced by this ATP-binding cassette transporter, 5 and most of them induce cell death in a caspase-independent manner, 6 albeit a few drugs are capable of activating caspases in P-gp-expressing cells. 7 Activation of the phosphatidylinositol 3-kinase (PI3K)/Aktsignaling pathway is another key factor, which plays a central role in cancer biology, conferring resistance both in vivo and in vitro to therapeutic treatments of various types of malignancies.…”

Section: Introductionmentioning

confidence: 99%

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

et al. 2008

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A significant impediment to the success of cancer chemotherapy is the occurrence of multidrug resistance, which, in many cases, is attributable to overexpression of membrane transport proteins, such as the 170-kDa P-glycoprotein (P-gp). Also, upregulation of the phosphatidylinositol 3-kinase (PI3K)/Aktsignaling pathway is known to play an important role in drug resistance, and has been implicated in the aggressiveness of a number of different cancers, including T-acute lymphoblastic leukemia (T-ALL). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine (a synthetic alkylphospholipid), on human T-ALL CEM cells (CEM-R), characterized by both overexpression of P-gp and constitutive upregulation of the PI3K/Akt network. Perifosine treatment induced death by apoptosis in CEM-R cells. Apoptosis was characterized by caspase activation, Bid cleavage and cytochrome c release from mitochondria. The proapoptotic effect of perifosine was in part dependent on the Fas/FasL interactions and c-Jun NH 2 -terminal kinase (JNK) activation, as well as on the integrity of lipid rafts. Perifosine downregulated the expression of P-gp mRNA and protein and this effect required JNK activity. Our findings indicate that perifosine is a promising therapeutic agent for treatment of T-ALL cases characterized by both upregulation of the PI3K/Akt survival pathway and overexpression of P-gp.

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The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines

Cited by 30 publications

References 24 publications

Mechanisms of Chromosome Congression during Mitosis

Mechanisms of Chromosome Congression during Mitosis

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

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