Acute myeloid leukemia (AML) represents a malignant blood tumor that originates from myeloid hematopoietic stem cells where there is a disruption in normal cell proliferation and differentiation among myeloid precursor cells inside the bone marrow.
- Daunorubicin or doxorubicin: Anthracycline antibiotics like daunorubicin and doxorubicin can disrupt DNA replication.
- Cytarabine (Ara-C): a nucleoside analog that inhibits DNA synthesis.
| Drugs |
Resistance mechanism |
Key molecules/mechanisms |
| Daunorubicin |
Enhanced drug efflux |
P-gp (ABCB1) |
|
Decreased or mutated topoisomerase II expression |
Topo II |
|
Enhanced antioxidant system |
GSH, SOD, etc. |
|
Abnormal apoptosis signaling pathway |
p53, Bcl-2, Mcl-1 |
| Cytarabine |
Decreased expression of nucleoside transporters |
hENT1 |
|
Downregulation of dCK |
Deoxycytidine kinase |
|
Enhanced drug metabolism |
CDA, 5'-NT |
|
Enhanced DNA repair capacity |
NER, BER, etc. |
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Acute Myeloid Leukemia
AML represents a blood cancer which targets myeloid cells within bone marrow leading to fast growth of abnormal white blood cells. AML shows disrupted differentiation of myeloid progenitor cells together with fast growth of immature myeloid cells and primitive cell build-up in bone marrow. AML progresses much more quickly than chronic leukemia because its symptoms typically emerge over a span of weeks. Symptoms of AML may include:
- Fatigue and weakness
- Anemia (causing paleness)
- Bleeding or bruising (such as bleeding gums, nosebleeds, etc.)
- Increased frequency of infections (due to abnormal white blood cell function)
- Fever
- Weight loss
- Bone or joint pain
Mechanism of Daunorubicin Resistance
The anthracycline antibiotic daunorubicin attaches to DNA strands while inhibiting topoisomerase II, leading to DNA breaks that trigger apoptosis. Daunorubicin is a versatile chemotherapeutic agent used to treat a variety of cancer types. The development of cancer cell resistance to daunorubicin is a major obstacle to effective clinical treatment. Daunorubicin resistance develops through several major mechanisms.
Cytarabine (Ara-C) Resistance Mechanism
Cytarabine (Ara-C) serves as the principal medication to treat acute lymphoblastic leukemia along with acute myeloid leukemia. Drug resistance development represents a significant obstacle to cytarabine's clinical usage. Several factors contribute to the development of resistance to cytarabine.
Changes in Metabolic Pathways
Cytarabine must be transformed into its active Ara-CTP form inside the cell although some cells diminish this conversion through altered metabolic enzyme expression like increased dephosphorylase levels which results in lesser active cytarabine production. The activity of cytarabine will be influenced by deacylation processes.
Enhanced Repair Mechanisms
Leukemic cells protect themselves against cytarabine-induced DNA damage through heightened DNA repair mechanism activation.
Changes in Cell Signaling Pathways
The modification of cell signaling routes that manage cell growth and death functions (including pathways like MAPK and PI3K/AKT) Modifications to cell signaling pathways related to proliferation and survival might make cells less reactive to cytarabine treatment. Cells may withstand cytarabine-induced cell death by strengthening anti-apoptotic signal pathways.
Genetic and epigenetic changes
Genetic mutations found in gene regulation, metabolism or drug target genes and epigenetic modifications including DNA methylation and histone changes can alter cellular sensitivity to cytarabine.
Drug Combination
AML cells can develop multiple resistance mechanisms because daunorubicin and cytarabine are frequently administered together in combination chemotherapy treatments like the "7+3 regimen". Possible countermeasures include:
- Utilize P-gp inhibitors including Verapamil and Cyclosporin A as part of treatment strategies.
- Administer Bcl-2 inhibitors like Venetoclax to increase apoptotic cell death.
- Ara-C effectiveness can be boosted by employing dCK activators or CDA inhibitors.
- Apply DNMT inhibitors along with HDAC inhibitors to overcome drug resistance in cells.
Resistance Mechanisms and Treatment Strategies for Combination of Daunorubicin and Cytarabine
The drugs daunorubicin and cytarabine serve as standard treatment options in acute leukemia cases particularly for acute myeloid leukemia (AML). Clinical treatment frequently encounters the challenge of drug resistance. Leukemia cells release therapeutic drugs and decrease their effective concentration by upregulating multidrug resistance proteins which include P-glycoprotein.
Cancer cells can speed up drug metabolism while diminishing drug effectiveness through excessive metabolic enzyme production including cytosine deaminase. Alterations in genes that control cell growth and demise mechanisms (including TP53 or NRAS genes) can produce resistance to medical treatments. The activation of specific survival signaling pathways enables cancer cells to resist drug damage with pathways including PI3K/Akt being frequently engaged. Treatment resistance can be overcome by utilizing combination therapy with drugs that target FLT3 and BCL-2.
The effectiveness of tumor cell resistance can be improved through the application of epigenetic medications like HDAC inhibitors combined with immunotherapies including CAR-T cell therapy. When faced with drug resistance healthcare providers may modify the chemotherapy approach by increasing dosages or prolonging treatment cycles and switching administration routes to options like intravenous or oral delivery.).
References
- Lancet, J., et al. CPX-351 versus 7+ 3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. The Lancet Haematology. 2021, 8(7): e481-e491.
- Arwanih, E., et al. Resistance mechanism of acute myeloid leukemia cells against daunorubicin and cytarabine: a literature review. Cureus. 2022, 14(12).
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