Wnt/β‑catenin inhibition reverses multidrug resistance in pediatric acute lymphoblastic leukemia

Abstract

Although ~80% of newly diagnosed pediatric patients with acute lymphoblastic leukemia (ALL) become disease-free following appropriate treatment, relapses frequently occur, with dismal prognosis. Therefore, it is urgent to develop novel therapeutic modalities. Resistance to chemotherapy is a major obstacle for the treatment of relapsed ALL. It has been indicated that Wnt pathway is potentially associated with leukemia recurrence. In the current study, a vincristine (VCR)-resistant variant of the human ALL cell line BALL-1 (BALL-1/VCR) that also had relatively specific resistance to both doxorubicin and etoposide was generated. Over-activation of the Wnt/β-catenin signaling pathway was observed in BALL-1/VCR cells, whereas Dickkopf-related protein 1 selectively suppressed the Wnt signaling pathway and sensitized the response of BALL-1/VCR to anticancer agents. In addition, prednisolone exposure in combination with Wnt inhibition restored chemo-sensitivity in relapsed ALL blasts. Since the resistance of BALL-1/VCR cells is potentially attributed to the overexpression of MDR-associated protein 1 (MRP1), the development of drug resistance in relapsed ALL may associated with the overexpression of MRP1 and P-glycoprotein. The results of this study demonstrated that, as a potential candidate to mimic relapsed ALL, BALL-1/VCR could be used in further research, while Wnt-inhibition may become a promising therapeutic approach for treating ALL.

Identification of Potential Signatures and Their Functions for Acute Lymphoblastic Leukemia: A Study Based on the Cancer Genome Atlas

“…As for the Wnt signaling pathway, it was significantly correlated with the pathogenesis of ALL ( Montano et al, 2018 ). Recent findings reported that inhibiting Wnt/β catenin could reverse multidrug resistance in children ALL ( Fu et al, 2019 ). Moreover, the pathway is regulated by many factors.…”

Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

“…Some chemotherapeutic agents that might be used for ALL treatment (such as doxorubicin, vinblastine or camptothecin) [20] increase the level of oxidative stress, as their antitumor activity depends directly on H 2 O 2 -induced apoptosis [21][22][23][24][25]. One of the critical cytoprotective proteins induced in response to oxidative stress is heme oxygenase-1 (HO-1, encoded by HMOX1 gene localized on chromosome 22q12) [26][27][28][29][30].…”

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

“…Mediator of drug resistance -Notch inhibitors sensitize B-ALL cells to chemotherapy (Takam Kamga et al, 2019b). -Wnt inhibition sensitizes B-ALL to chemotherapy (Fu et al, 2019).…”

“…The functional outcome of this Wnt/Notch crosstalk between MSCs and B-ALL or AML cells is the induction of leukemia cell proliferation, survival and chemoresistance. Consequently, Wnt and/or Notch inhibition through pharmacological modulators, including small molecules inhibitors Niclosamide,GSIs) and Notch blocking antibodies, may sensitize leukemia cells to drug treatment, thus abrogating the protective role of MSC monolayer (Kamdje et al, 2011;Takam Kamga et al, 2016a, 2020Fu et al, 2019). This antileukemic role requires the production of reactive oxygen species (ROS) and the modulation of prosurvival proteins, such as mTor, NF-κB, STAT-3, and Erk (Kamdje et al, 2011;Takam Kamga et al, 2016a,b).…”