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.
Highlights
Relapse and refractory diseases are major clinical challenges during the management of acute myeloid leukemia (AML) patients, and they prevent an optimized response to current treatments
A direct correlation between lysosome function and gemtuzumab ozogamicin-induced cytotoxicity was observed and forced activation of lysosomes led to a synergistic effect with gemtuzumab ozogamicin[106], demonstrating that these lysosomal-dependent conjugate approaches used as monotherapy may be of limited interest in AML
Refractory and relapse disease are still the main clinical challenges faced in AML
Summary
Relapse and refractory diseases are major clinical challenges during the management of acute myeloid leukemia (AML) patients, and they prevent an optimized response to current treatments. Higher concentrations are required to achieve therapeutically relevant concentrations, increasing side effects in patients, and promoting secondary chemotherapy resistance Treatment with these types of drugs induces expansion of the lysosomal compartment, thereby enhancing their lysosomal sequestration capacity and further increasing chemoresistance, constituting a feedback loop[78-80]. Cationic amphiphilic antihistamines simultaneously disrupt both lysosomes and mitochondria, based on their physico-chemical properties, inducing both apoptosis and autophagy[93] Both the specific cationic amphiphilic antihistamines and mefloquine spare healthy blood cells, confirming the differential effect of lysosomal disruptors in AML and the existence of a preclinically-validated therapeutic window. Lysosomal expansion is accompanied by an increase in pH, inducing exocytosis and, clearance of chemotherapy from cells Both mechanisms prevent chemotherapeutic agents from directly interacting with their molecular targets, commonly located in the nucleus. A direct correlation between lysosome function and gemtuzumab ozogamicin-induced cytotoxicity was observed and forced activation of lysosomes led to a synergistic effect with gemtuzumab ozogamicin[106], demonstrating that these lysosomal-dependent conjugate approaches used as monotherapy may be of limited interest in AML
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