Multidrug Resistance in Acute Myeloid Leukemia: Potential New Therapeutics

Weisburg, Jeffrey H.

doi:10.2967/jnumed.107.050153

Cited by 6 publications

(3 citation statements)

References 21 publications

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“…(4) MJ activated the MAPK pathway in the human myelocytic leukemia cell line HL-60, but the outcome of this event was cell differentiation rather than apoptosis [41]; the differentiation effect was inhibited by PD98059, a MEK1 inhibitor, confirming the involvement of MAPK/ERK pathway in this MJ-mediate activity [41]. Acute myeloid leukemia (AML) is one of the worst forms of leukemia (AML blasts are immature myeloid cells), because it is largely resistant to chemotherapeutic drugs and other forms of therapy [176]. These cells can be induced to differentiate into normal, functional myeloid cells by different chemicals; unfortunately, many of these chemicals are too toxic to be used clinically (http://www.cancer.org/acs/groups/cid/documents/webcontent/003110-pdf.pdf).…”

Section: Effects Of Jasmonates On Mammalian Cancer Cellsmentioning

confidence: 99%

Methyl Jasmonate: Putative Mechanisms of Action on Cancer Cells Cycle, Metabolism, and Apoptosis

Cesari

Carvalho

Rodrigues

et al. 2014

International Journal of Cell Biology

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Methyl jasmonate (MJ), an oxylipid that induces defense-related mechanisms in plants, has been shown to be active against cancer cells both in vitro and in vivo, without affecting normal cells. Here we review most of the described MJ activities in an attempt to get an integrated view and better understanding of its multifaceted modes of action. MJ (1) arrests cell cycle, inhibiting cell growth and proliferation, (2) causes cell death through the intrinsic/extrinsic proapoptotic, p53-independent apoptotic, and nonapoptotic (necrosis) pathways, (3) detaches hexokinase from the voltage-dependent anion channel, dissociating glycolytic and mitochondrial functions, decreasing the mitochondrial membrane potential, favoring cytochrome c release and ATP depletion, activating pro-apoptotic, and inactivating antiapoptotic proteins, (4) induces reactive oxygen species mediated responses, (5) stimulates MAPK-stress signaling and redifferentiation in leukemia cells, (6) inhibits overexpressed proinflammatory enzymes in cancer cells such as aldo-keto reductase 1 and 5-lipoxygenase, and (7) inhibits cell migration and shows antiangiogenic and antimetastatic activities. Finally, MJ may act as a chemosensitizer to some chemotherapics helping to overcome drug resistant. The complete lack of toxicity to normal cells and the rapidity by which MJ causes damage to cancer cells turn MJ into a promising anticancer agent that can be used alone or in combination with other agents.

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Section: Effects Of Jasmonates On Mammalian Cancer Cellsmentioning

confidence: 99%

Methyl Jasmonate: Putative Mechanisms of Action on Cancer Cells Cycle, Metabolism, and Apoptosis

Cesari

Carvalho

Rodrigues

et al. 2014

International Journal of Cell Biology

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“…Treatment of resistant leukemic cells is usually very difficult because the range of resistance generally extends even to drugs to which leukemic cells have never been exposed. 9…”

Section: Discussionmentioning

confidence: 99%

Role of MRP-1 and GST-Pi in MDR and their inhibition by indomethacin in AML

Ebeed

Sadek

Zaher

et al. 2017

Alexandria Journal of Medicine

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Background: MDR continues to be a major challenge to effective chemotherapeutic interventions against cancer. Defining major factor contributing to MDR and inhibiting their action may thus be used for reversing MDR. Aim: This work aimed to evaluate the role played by MRP-1 and GST-Pi in MDR, and to explore the possible role of indomethacin as an inhibitor of chemotherapy resistance in patients with AML. Subjects and methods: The study included 2 groups, one included 20 healthy volunteers and the second included 50 AML patients. All patients received one cycle of standard induction chemotherapy, then regrouped according to their response to either CR group or unremitted group. Unremitted patients received a second cycle of chemotherapy combined with indomethacin. From each subject a blood sample was drawn before and after the 1st cycle of chemotherapy and after the 2nd cycle. From blood, mononuclear cells were separated, mRNA was extracted, and RT-PCR was carried out to detect GST-Pi and MRP-1 gene expression. Results: GST-Pi expression in CR group was 60% before therapy that significantly decreased to 30% after therapy. While in unremitted group, its expression significantly increased from 30% before to 80% after therapy. GST-Pi positive patients had a significantly lower overall and disease free survival time than GST-Pi negative patients (P = 0.000 and 0.039, respectively). While MRP-1 expression was so low (20%) and remained unchanged after therapy in both groups. MRP-1 expression did not affect overall or disease free survival. Taking indomethacin with 2nd cycle of chemotherapy in unremitted patients resulted in a significant inhibition of GST-Pi expression and a significantly longer overall survival time than those taking 2nd cycle chemotherapy alone (P = 0.034).

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“…P-glycoprotein is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity (Nørgaard, 2000). It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs (Weisburg, 2008;Talpaz, 2009). Therefore, targeting the AKT or NF-kB pathway alone may not be sufficient to induce apoptosis of cancer cells and combinations of various inhibitors maybe required to achieve the favorite effect.…”

Section: Introduction *mentioning

confidence: 99%