Antitumoral Activity of 13-Demethyl or 13-Substituted Analogues of All-trans Retinoic Acid and 9-cis Retinoic Acid in the Human Myeloid Leukemia Cell Line HL-60

The mechanism(s) by which acute promyelocytic leukemia (APL) cells acquire resistance to all-trans retinoic acid (ATRA) is poorly understood. We describe here an APL cell line, named NB4.306, that shows resistance to the anti-proliferative action of ATRA. This cell line is also operationally resistant to most ATRA-induced phenotypic modifications (CD11b, CD11c, CD13, and CD33). No significant differences in ATRA intracellular accumulation, efflux, or metabolism were found between NB4.306 and the parent NB4 cell line that could explain the observed resistance of the NB4.306 line. The NB4.306 cell line was found to be positive for the t15;17 translocation and showed the usual pml/RAR alpha fusion bands in both Southern and Northern blot assays, but expressed no detectable amount of the usual pml/RAR alpha protein, as assayed by Western blot analysis using an anti-RAR alpha antibody. These results were confirmed in 14 of 14 clones obtained from the NB4.306 cell line, while 30 of 30 clones obtained from the parental NB4 line expressed the usual 110-Kd fusion polypeptide. It is concluded that the occurrence of resistance to ATRA in the NB4.306 cell line is closely associated to the loss of expression of the intact pml/RAR alpha protein.

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Bexarotene derivatives modify responses in acute myeloid leukemia

10.1101/2021.05.17.444475 ◽

2021 ◽

Author(s):

Gayla Hadwiger ◽

Orsola di Martino ◽

Margaret Ashley Ferris ◽

Anh Vu ◽

Thomas E. Frederick ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Leukemia Cell ◽

Promyelocytic Leukemia ◽

Leukemia Cell Line ◽

Structure Activity ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acute Myeloid

The retinoids all-trans retinoic acid (ATRA) and bexarotene are active in acute myeloid leukemia (AML), but responses beyond acute promyelocytic leukemia (APL) have been more modest than APL responses. To determine whether chemical modification of bexarotene might augment retinoid responses in AML, we screened a series of 38 bexarotene derivatives for activity in a mouse MLL-AF9 leukemia cell line, which exhibits strong synergistic sensitivity to the combination of ATRA and bexarotene. We found that RXRA potency correlated with anti-leukemic activity and that only one compound (103-4) with dual RARA/RXRA activity was capable of ATRA-independent anti-leukemic activity. We evaluated bioisostere and cyclohexane modifications for potential resistance to P450 metabolism and found that bioisosteres reduced potency and that bezopyran, cyclopentane, and cyclohexene modifications only modestly reduced susceptibility to metabolism. Collectively, these studies provide a map of the structure-activity relationships of bexarotene with outcomes related to RXRA and RARA activity, corepressor binding, compound stability, and anti-leukemic potential.

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Occurrence of resistance to retinoic acid in the acute promyelocytic leukemia cell line NB4 is associated with altered expression of the pml/RAR alpha protein

Blood ◽

10.1182/blood.v82.5.1573.1573 ◽

1993 ◽

Vol 82 (5) ◽

pp. 1573-1577 ◽

Cited By ~ 75

Author(s):

S Dermime ◽

F Grignani ◽

M Clerici ◽

C Nervi ◽

G Sozzi ◽

...

Keyword(s):

Retinoic Acid ◽

Cell Line ◽

Acute Promyelocytic Leukemia ◽

Leukemia Cell ◽

Promyelocytic Leukemia ◽

Leukemia Cell Line ◽

Altered Expression ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Promyelocytic Leukemia Cell Line

Abstract The mechanism(s) by which acute promyelocytic leukemia (APL) cells acquire resistance to all-trans retinoic acid (ATRA) is poorly understood. We describe here an APL cell line, named NB4.306, that shows resistance to the anti-proliferative action of ATRA. This cell line is also operationally resistant to most ATRA-induced phenotypic modifications (CD11b, CD11c, CD13, and CD33). No significant differences in ATRA intracellular accumulation, efflux, or metabolism were found between NB4.306 and the parent NB4 cell line that could explain the observed resistance of the NB4.306 line. The NB4.306 cell line was found to be positive for the t15;17 translocation and showed the usual pml/RAR alpha fusion bands in both Southern and Northern blot assays, but expressed no detectable amount of the usual pml/RAR alpha protein, as assayed by Western blot analysis using an anti-RAR alpha antibody. These results were confirmed in 14 of 14 clones obtained from the NB4.306 cell line, while 30 of 30 clones obtained from the parental NB4 line expressed the usual 110-Kd fusion polypeptide. It is concluded that the occurrence of resistance to ATRA in the NB4.306 cell line is closely associated to the loss of expression of the intact pml/RAR alpha protein.

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