Synergistic decrease of clonal proliferation, induction of differentiation, and apoptosis of acute promyelocytic leukemia cells after combined treatment with novel 20-epi vitamin D3 analogs and 9-cis retinoic acid.

Elstner, E; Linker-Israeli, M; Lê, Jennifer; Umiel, Tehila; Michl, Patrick; Said, Jonathan; Binderup, Lise; Reed, John C.; Koeffler, H. Phillip

doi:10.1172/jci119164

Cited by 65 publications

(44 citation statements)

References 63 publications

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“…We had chosen to investigate the combination of 9-cRA with KH1060 since synergistic growth inhibition had been found in APL cells. 11 However, in non-M3 AML cells we did not observe consistent complementary effects for the two compounds. The inhibitory effect of 9-cRA alone on the growth of non-M3 AML cells has been described by others 13 and our findings are consistent with theirs.…”

Section: Figurecontrasting

confidence: 59%

“…6,9,11,[20][21][22] However, one drug resistant HL60 subline underwent differentiation without loss of bcl-2 protein 31 and transfection of bcl-2 does not inhibit differentiation. 19 Using flow cytometric protein measurement in conjunction with cell cycle analysis, we were able to examine protein expression on G0/G1 cells, thus ruling out the generalised protein loss of cell decay.…”

Section: Figurementioning

confidence: 99%

“…6,9-11 9-cis-retinoic acid (9cRA), a stereoisomer of ATRA, inhibits clonal growth in leukaemic cell lines and primary AML cells. 9,[11][12][13] N-(4-hydroxyphenyl) retinamide (4HPR) induces apoptosis in leukaemic cell lines, including ATRA-resistant lines. 14,15 The combination of KH1060 and 9cRA proved more active in inducing differentiation and apoptosis and suppressing the colony growth of HL60 and NB4 cells than either agent alone.…”

Section: Introductionmentioning

confidence: 99%

“…14,15 The combination of KH1060 and 9cRA proved more active in inducing differentiation and apoptosis and suppressing the colony growth of HL60 and NB4 cells than either agent alone. 9,11 We therefore investigated whether this combination, as well as the agents used singly, would have an effect on primary AML cells.…”

Section: Introductionmentioning

confidence: 99%

“…[16][17][18][19] Bcl-2 is downregulated in leukaemic cells treated with differentiating agents, 6,9,11,[20][21][22][23] and this mechanism may underlie the increased sensitivity of leukaemic cells to the combination of cytotoxic drugs and ATRA. 17 In this study, we have therefore investigated the expression of bcl-2, and also bcl-x and bax, in AML cells treated with KH1060 and 9 cRA.…”

Section: Introductionmentioning

confidence: 99%

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Blast maturity and CD34 expression determine the effects of the differentiating agents KH1060 and 9-cis-retinoic acid on the differentiation and clonogenicity of non-M3 acute myeloid leukaemia cells

1998

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The vitamin D analogue KH1060 and the retinoids all-trans retinoic acid (ATRA), 9-cis-retinoic acid (9-cRA) and 4-hydroxyphenyl retinamide (4-HPR) induce differentiation and/or apoptosis and inhibit clonal growth of acute promyelocytic leukaemia cells. We have studied the effects of these agents in vitro on cells from 12 patients with other forms of acute myeloblastic leukaemia (AML). Treatment with KH1060 (10 −6 M) caused decreases in cell viability in suspension culture to a median of 44% of control values (P = 0.02). However, retinoids had little effect. Subsequent clonal growth in semi-solid medium was inhibited to 5% (median) of control with 10 −6 M KH 1060 (P = 0.03) and to 73% with 10 −6 M 9-cRA (P = 0.01). Further inhibition of clonal growth by the combination of 5 × 10 −7 M 9-cRA and 5 × 10 −7 M KH1060 was only noted in one case. Following the primary suspension culture, cells from 6/6 CD34 positive samples grew in semi-solid cultures without analogues, whereas cells from 3/6 CD34 negative cultures grew. 10 −6 M KH1060 completely abolished colony growth in all three CD34 negative samples and 10 −6 M 9-cRA inhibited the number of colonies to a median of 11% of control values. In the six CD34 positive samples median colony growth was inhibited to 36% of control values by KH1060 and to 83% of control values by 9-cRA. CD11b expression was increased by 210% (median) with 9-cRA and by 90% (median) with KH1060 in early to intermediate myeloblast (M0, M1, M2) clones. A different pattern was noted in more mature (M4, M5, M6) clones: here there was little or no increase in CD11b expression induced by retinoids or KH1060, but the ratio of apoptotic to viable CD11b + cells, measured by CD11b/7-AAD double staining, was increased in 6/6 cases treated with KH1060 or the combination of 9-cRA and KH 1060, and in 5/6 cases treated with 9-cRA. No overall significant change in bcl-2 or bax expression on G0/G1 cells was found after 3 days' suspension culture with the analogues. However bcl-x was downregulated in G0/G1 cells treated with KH1060 (median bcl-x relative fluorescence intensity = 45.3 in cells treated with KH1060, compared with 65.7 in control wells, P = 0.028). We conclude that CD34 + samples are relatively resistant to the growth inhibition induced by KH1060 and 9-cRA. However, downregulation of bcl-x in cells which have survived treatment with KH1060 may increase the susceptibility of the remaining leukaemic cells to cytotoxic drugs.

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Section: Figurecontrasting

confidence: 59%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Blast maturity and CD34 expression determine the effects of the differentiating agents KH1060 and 9-cis-retinoic acid on the differentiation and clonogenicity of non-M3 acute myeloid leukaemia cells

1998

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Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells

et al. 1999

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Inhibition of proliferation and induction of differentiation of osteoblastic cells by a novel 1,25-dihydroxyvitamin D3 analog with an extensively modified side chain (CB1093)

et al. 1998

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1,25-Dihydroxyvitamin D3 (1,25D) is involved in the regulation of proliferation and differentiation of a variety of cell types including cancer cells. In recent years, numerous new vitamin D3 analogs have been developed in order to obtain favorable therapeutic properties. The effects of a new 20-epi analog, CB1093 (20-epi-22-ethoxy-23-yne-24a,26a,27a-trihomo+ ++-1alpha,25(OH)2D3), on the proliferation and differentiation of human MG-63 osteosarcoma cell line were compared here with those of the parent compound 1,25D. Proliferation of the MG-63 cells was inhibited similarly by 22%, 50% and 59% after treatment with 0.1 microM 1,25D or CB1093 for 48 h, 96 h, and 144 h, respectively. In transfection experiments, the compounds were equipotent in stimulating reporter gene activity under the control of human osteocalcin gene promoter. In cell culture experiments, however, CB1093 was more potent than 1,25D at low concentrations and more effective for a longer period of time in activating the osteocalcin gene expression at mRNA and protein levels. Also, a 6-h pretreatment and subsequent culture for up to 120 h without 1,25D or CB1093 yielded higher osteocalcin mRNA and protein levels with analog-treated cells than with 1,25D-treated cells. The electrophoretic mobility shift assay (EMSA) revealed stronger VDR-VDRE binding with analog-treated MG-63 cells than with 1,25D-treated cells. The differences in the DNA binding of 1,25D-bound vs. analog-bound VDR, however, largely disappeared when the binding reactions were performed with recombinant hVDR and hRXRbeta proteins. These results demonstrate that the new analog CB1093 was equally or even more effective than 1,25D in regulating all human osteosarcoma cell functions ranging from growth inhibition to marker gene expression and that the differences in effectivity most probably resulted from interactions of the hVDR:hRXRbeta-complex with additional nuclear proteins.

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Synergistic decrease of clonal proliferation, induction of differentiation, and apoptosis of acute promyelocytic leukemia cells after combined treatment with novel 20-epi vitamin D3 analogs and 9-cis retinoic acid.

Cited by 65 publications

References 63 publications

Blast maturity and CD34 expression determine the effects of the differentiating agents KH1060 and 9-cis-retinoic acid on the differentiation and clonogenicity of non-M3 acute myeloid leukaemia cells

Blast maturity and CD34 expression determine the effects of the differentiating agents KH1060 and 9-cis-retinoic acid on the differentiation and clonogenicity of non-M3 acute myeloid leukaemia cells

Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells

Inhibition of proliferation and induction of differentiation of osteoblastic cells by a novel 1,25-dihydroxyvitamin D3 analog with an extensively modified side chain (CB1093)

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