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Updated: Aug 19, 2026
Modeling Chemotherapy Resistant Leukemia In Vitro
Published on: February 9, 2016
WEB-2086 and WEB-2170 trigger apoptosis in both ATRA-sensitive and -resistant promyelocytic leukemia cells and
A Laurenzana1, C Cellai, A M Vannucchi
1Department of Experimental Pathology and Oncology, University of Florence, Italy.
Abstract:
PAF-receptor antagonists WEB-2086 and WEB-2170 (WEBs) have been previously shown to induce differentiation in murine and human leukemia cells. The present study describes the apoptotic-differentiative effect of WEBs in all-trans-retinoic acid (ATRA)-sensitive (NB4) and -resistant (NB4-007-6 and NB4-MR4) acute promyelocytic leukemia (APL) cell lines as well as blasts from patients with t(15;17) APL. NB4 cells exposed to 0.5-1 mM WEBs underwent striking growth arrest and massive apoptosis without appreciable differentiation; IC50 values after 3-day treatment of NB4 were 0.4 and 0.25 mM for WEB-2086 and WEB-2170, respectively. WEBs induced apoptosis also in the two ATRA-resistant NB4-007-6 and NB4-MR4 cell lines and in blasts from patients with t(15;17) APL. Moreover, subapoptotic WEBs acted synergistically with low-dose (0.025-0.05 microM) ATRA; this allowed to increase ATRA differentiation potential up to 40-fold and to improve both number and intensity of NBT-positive NB4 cells at definitely higher levels than with 1 muM ATRA alone. The powerful antiproliferative-apoptotic activities of WEBs in vitro on ATRA-sensitive, ATRA-resistant APL cells and blasts from patients with APL as well as drug capabilities to enhance ATRA differentiation potential suggested that these agents also due to their recognized tolerability in vivo might improve, alone or in combination, clinical treatment of APL.
Insights
PAF-receptor antagonists WEB-2086 and WEB-2170 induce apoptosis and growth arrest in acute promyelocytic leukemia cells. These agents enhance all-trans-retinoic acid differentiation, suggesting potential for improved APL treatment.
Area of Science:
- Hematology
- Pharmacology
- Cell Biology
Background:
- Platelet-activating factor (PAF) receptor antagonists WEB-2086 and WEB-2170 (WEBs) have demonstrated leukemia cell differentiation.
- Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation and can develop resistance to standard therapies like all-trans-retinoic acid (ATRA).
Purpose of the Study:
- To investigate the apoptotic and differentiative effects of WEBs in ATRA-sensitive and ATRA-resistant APL cell lines and patient samples.
- To evaluate the synergistic potential of WEBs in combination with low-dose ATRA.
Main Methods:
- Treatment of NB4 (ATRA-sensitive), NB4-007-6, and NB4-MR4 (ATRA-resistant) APL cell lines with WEBs.
- Analysis of apoptosis, growth arrest, and differentiation markers (e.g., NBT positivity).
- Combination studies with WEBs and varying doses of ATRA.
Main Results:
- WEBs induced significant growth arrest and apoptosis in NB4 cells at concentrations of 0.5-1 mM, with IC50 values of 0.4 mM (WEB-2086) and 0.25 mM (WEB-2170).
- Apoptosis was also observed in ATRA-resistant cell lines and primary APL patient blasts.
- Sub-apoptotic doses of WEBs synergized with low-dose ATRA, enhancing differentiation up to 40-fold compared to ATRA alone.
Conclusions:
- WEBs exhibit potent antiproliferative and apoptotic activities against both ATRA-sensitive and ATRA-resistant APL cells.
- The synergistic effect with ATRA suggests that WEBs could improve the clinical treatment of APL, potentially offering a better tolerability profile.