Lysosome-mediated chemoresistance in acute myeloid leukemia

Abstract

Despite the outstanding advances in understanding the biology underlying the pathophysiology of acute myeloid leukemia (AML) and the promising preclinical data published lastly, AML treatment still relies on a classic chemotherapy regimen largely unchanged for the past five decades. Recently, new drugs have been approved for AML, but the real clinical benefit is still under evaluation. Nevertheless, primary refractory and relapse AML continue to represent the main clinical challenge, as the majority of AML patients will succumb to the disease despite achieving a complete remission during the induction phase. As such, treatments for chemoresistant AML represent an unmet need in this disease. Although great efforts have been made to decipher the biological basis for leukemogenesis, the mechanism by which AML cells become resistant to chemotherapy is largely unknown. The identification of the signaling pathways involved in resistance may lead to new combinatory therapies or new therapeutic approaches suitable for this subset of patients. Several mechanisms of chemoresistance have been identified, including drug transporters, key secondary messengers, and metabolic regulators. However, no therapeutic approach targeting chemoresistance has succeeded in clinical trials, especially due to broad secondary effects in healthy cells. Recent research has highlighted the importance of lysosomes in this phenomenon. Lysosomes’ key role in resistance to chemotherapy includes the potential to sequester drugs, central metabolic signaling role, and gene expression regulation. These results provide further evidence to support the development of new therapeutic approaches that target lysosomes in AML.

A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia

“…As shown in Figure 2 , the EDK-87 and EDK-88 compounds effectively reduced the disease progression in mice xenotransplanted with either AML model, and significantly reduced the leukemic burden in the bone marrow ( Figure 2 A,B and Figure S2A,B ), regardless of the chemoresistance and in vivo proliferation rate (EDK-87: 58.44%; EDK-88: 43.06%). The engraftment growth was disrupted in the chemoresistant MonoMac1 AML model ( Figure 2 A) compared to the deceleration observed in the chemosensitive KG1 model ( Figure 2 B); since lysosomes have recently been implicated in chemoresistance processes [ 20 ], and because previously described lysosomotropic antihistamines [ 14 ] were used as the scaffold for the drug design program, the lysosomal compartment was studied in response to resistance acquisition via long-term cytarabine exposure. As suggested from the efficiency assays, a significant increase in lysosomal mass was observed upon the acquisition of cytarabine resistance ( Supplementary Figure S2B ).…”

Galectin-9 has non-apoptotic cytotoxic activity towards Acute Myeloid Leukemia independent of cytarabine resistance

“…AraC-resistant (AraC-Res) AMLs often have defects in the apoptosis pathway [23]. Furthermore, lysosomes are known to contribute to therapy resistance by drug sequestration [24]. Since Gal-9 induces apoptosis-independent cell death and acts as a lysosomal inhibitor, we hypothesized that Gal-9 may retain cytotoxicity against AraC-Res AML cells.…”

“…In line with this, Gal-9 clearly accumulated in the lysosomes of AML cells (Figure 4L), suggesting that Gal-9 acts as a lysomotrophic agent. Interestingly, recent studies highlight that targeting the lysosomes may be a potential novel therapeutic strategy for the treatment of AML [24][25][26][27], with CQ being the agent of choice in most studies. Therefore, the cytotoxic potential of CQ and Gal-9 was compared, with 150nM and 300nM Gal-9 (Suppl.…”

Galectin-9 has non-apoptotic cytotoxic activity towards Acute Myeloid Leukemia independent of cytarabine resistance

“…4L), suggesting that Gal-9 acts as a lysomotrophic agent. Interestingly, recent studies highlight that targeting the lysosomes may be a potential novel therapeutic strategy for the treatment of AML [24][25][26][27], with CQ being the agent of choice in most studies. Therefore, the cytotoxic potential of CQ and Gal-9 was compared, with 150nM and 300nM Gal-9 (Suppl.…”

“…Gal-9 Is Cytotoxic For Arac-resistant Aml And Potentiates The E cacy Of Azacitidine AraC-resistant (AraC-Res) AMLs often have defects in the apoptosis pathway [23]. Furthermore, lysosomes are known to contribute to therapy resistance by drug sequestration [24]. Since Gal-9 induces apoptosis-independent cell death and acts as a lysosomal inhibitor, we hypothesized that Gal-9 may retain cytotoxicity against AraC-Res AML cells.…”