Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms

Author(s)

Vicari, Hugo Passos ; Lima, Keli ; Costa-Lotufo, Leticia Veras ; Machado-Neto, Joao Agostinho

• Document type: Journal article
• Source: CANCERS; v. 14, n. 24, p. 15-pg., 2022-12-01.

Abstract

Simple Summary Hematologic neoplasms comprise a heterogeneous group of diseases that interfere with normal blood production. Treating patients who fail available therapies for these diseases is an ongoing challenge. Thus, the search for new treatment options is urgent, and drug repositioning is emerging as an attractive strategy for finding new effective drugs. Eribulin is a drug that acts on microtubules, and it is used in solid tumors, and its safety is known. In the present study, we provide evidence of the effects of eribulin on hematologic cancers and identify the potential biomarkers of responsiveness. Our study indicates that eribulin is a candidate blood cancer drug for repositioning. Despite the advances in understanding the biology of hematologic neoplasms which has resulted in the approval of new drugs, the therapeutic options are still scarce for relapsed/refractory patients. Eribulin is a unique microtubule inhibitor that is currently being used in the therapy for metastatic breast cancer and soft tissue tumors. Here, we uncover eribulin's cellular and molecular effects in a molecularly heterogeneous panel of hematologic neoplasms. Eribulin reduced cell viability and clonogenicity and promoted apoptosis and cell cycle arrest. The minimal effects of eribulin observed in the normal leukocytes suggested selectivity for malignant blood cells. In the molecular scenario, eribulin induces DNA damage and apoptosis markers. The ABCB1, ABCC1, p-AKT, p-NF kappa B, and NF kappa B levels were associated with responsiveness to eribulin in blood cancer cells, and a resistance eribulin-related target score was constructed. Combining eribulin with elacridar (a P-glycoprotein inhibitor), but not with PDTC (an NFkB inhibitor), increases eribulin-induced apoptosis in leukemia cells. In conclusion, our data indicate that eribulin leads to mitotic catastrophe and cell death in blood cancer cells. The expression and activation of MDR1, PI3K/AKT, and the NF kappa B-related targets may be biomarkers of the eribulin response, and the combined treatment of eribulin and elacridar may overcome drug resistance in these diseases. (AU)

• FAPESP's process: 21/01460-1 - Investigation of the antineoplastic potential of new drugs that modulate microtubule dynamics in Acute Myeloid Leukemia
• Grantee: Hugo Passos Vicari
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/23864-7 - Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/01700-2 - Functional investigation of Stathmin 1 in proliferation, differentiation and apoptosis in acute promyelocytic leukemia model
• Grantee: Hugo Passos Vicari
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 21/11606-3 - Investigation of the antineoplastic effects of novel PIP4K2 and HDAC inhibitors in hematologic malignancies
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants