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In Vitro Apoptotic Effects of Farnesyltransferase blockade in Acute Myeloid Leukemia Cells

View Article: PubMed Central - PubMed

ABSTRACT

Farnesyltransferase inhibitors (FTIs) are a class of oral anti-cancer drugs currently tested in phase I-II clinical trials for treatment of hematological malignancies. The in vitro effects of various FTIs (alpha-hydroxyfarnesylphosphonic acid, manumycin-A and SCH66336) were tested on CD34+ KG1a cell line and in primary acute myeloid leukemia (AML) cells from 64 patients. By cell viability and clonogeneic methylcellulose assays, FTIs showed a significant inhibitory activity in CD34+ KG1a and primary bone marrow (BM) leukemic cells from 56% of AML patients. FTIs also induced activation of caspase-3 and Fas-independent apoptosis, confirmed by the finding that inhibition of caspase-8 was not associated with the rescue of FTI-treated cells. We concluded that other cellular events induced by FTIs may trigger activation of caspase-3 and subsequent apoptosis, but the expression of proapoptotic molecules, as Bcl-2 and Bcl-XL, and antiapoptotic, as Bcl-X(s), were not modified by FTIs. By contrast, expression of inducible nitric oxide synthase (iNOS) was increased in FTI-treated AML cells. Our results suggest a very complex mechanism of action of FTIs that require more studies for a better clinical use of the drugs alone or in combination in the treatment of hematological malignancies.

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Related in: MedlinePlus

FTI exposure may modify p53 but not Bcl-2 pathway in AML cellsImmunoblotting of Bcl2, BclXL and BclXs from KG1a cells and total marrow cells of four AML patients cultured for 48 h in absence or in presence of FTIs, excludes the involvement of Bcl-2 pathway in FTI-induced apoptosis in human AML cells (A-B). Immunoblotting of p53 from KG1a cells and total marrow cells of four AML patients cultured for 48 h in absence or in presence of FTIs, shows the enhancement of p53, as quantified by densitometry scanning, in 2 out of 4 AML cases after FTI exposure (C).
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f6-tm-15-22: FTI exposure may modify p53 but not Bcl-2 pathway in AML cellsImmunoblotting of Bcl2, BclXL and BclXs from KG1a cells and total marrow cells of four AML patients cultured for 48 h in absence or in presence of FTIs, excludes the involvement of Bcl-2 pathway in FTI-induced apoptosis in human AML cells (A-B). Immunoblotting of p53 from KG1a cells and total marrow cells of four AML patients cultured for 48 h in absence or in presence of FTIs, shows the enhancement of p53, as quantified by densitometry scanning, in 2 out of 4 AML cases after FTI exposure (C).

Mentions: To explore whether FTI-induced apoptosis could be mediated by decreased expression of anti-apoptotic Bcl-2 and Bcl-X(L) or increasing in proapoptotic Bcl-X(S) proteins, AML cells were exposed for 48 hours to FTIs or control medium and Bcl-2 or Bcl-X(L)/(S) were measured. Quantification of protein banding by densitometry did not document changes in Bcl-2 protein expression in KG1a as well as in four primary BM AML samples after FTI exposure as compared to control cultures (Fig. 6A). Similarly, the expression of Bcl-X(L) and Bcl-X(S) did not show variations after FTI exposure (Fig. 5B). By contrast, in KG1a cells and few AML cases, an enhancement of p53 expression after FTI exposure was detected (Fig. 6C).


In Vitro Apoptotic Effects of Farnesyltransferase blockade in Acute Myeloid Leukemia Cells
FTI exposure may modify p53 but not Bcl-2 pathway in AML cellsImmunoblotting of Bcl2, BclXL and BclXs from KG1a cells and total marrow cells of four AML patients cultured for 48 h in absence or in presence of FTIs, excludes the involvement of Bcl-2 pathway in FTI-induced apoptosis in human AML cells (A-B). Immunoblotting of p53 from KG1a cells and total marrow cells of four AML patients cultured for 48 h in absence or in presence of FTIs, shows the enhancement of p53, as quantified by densitometry scanning, in 2 out of 4 AML cases after FTI exposure (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5120747&req=5

f6-tm-15-22: FTI exposure may modify p53 but not Bcl-2 pathway in AML cellsImmunoblotting of Bcl2, BclXL and BclXs from KG1a cells and total marrow cells of four AML patients cultured for 48 h in absence or in presence of FTIs, excludes the involvement of Bcl-2 pathway in FTI-induced apoptosis in human AML cells (A-B). Immunoblotting of p53 from KG1a cells and total marrow cells of four AML patients cultured for 48 h in absence or in presence of FTIs, shows the enhancement of p53, as quantified by densitometry scanning, in 2 out of 4 AML cases after FTI exposure (C).
Mentions: To explore whether FTI-induced apoptosis could be mediated by decreased expression of anti-apoptotic Bcl-2 and Bcl-X(L) or increasing in proapoptotic Bcl-X(S) proteins, AML cells were exposed for 48 hours to FTIs or control medium and Bcl-2 or Bcl-X(L)/(S) were measured. Quantification of protein banding by densitometry did not document changes in Bcl-2 protein expression in KG1a as well as in four primary BM AML samples after FTI exposure as compared to control cultures (Fig. 6A). Similarly, the expression of Bcl-X(L) and Bcl-X(S) did not show variations after FTI exposure (Fig. 5B). By contrast, in KG1a cells and few AML cases, an enhancement of p53 expression after FTI exposure was detected (Fig. 6C).

View Article: PubMed Central - PubMed

ABSTRACT

Farnesyltransferase inhibitors (FTIs) are a class of oral anti-cancer drugs currently tested in phase I-II clinical trials for treatment of hematological malignancies. The in vitro effects of various FTIs (alpha-hydroxyfarnesylphosphonic acid, manumycin-A and SCH66336) were tested on CD34+ KG1a cell line and in primary acute myeloid leukemia (AML) cells from 64 patients. By cell viability and clonogeneic methylcellulose assays, FTIs showed a significant inhibitory activity in CD34+ KG1a and primary bone marrow (BM) leukemic cells from 56% of AML patients. FTIs also induced activation of caspase-3 and Fas-independent apoptosis, confirmed by the finding that inhibition of caspase-8 was not associated with the rescue of FTI-treated cells. We concluded that other cellular events induced by FTIs may trigger activation of caspase-3 and subsequent apoptosis, but the expression of proapoptotic molecules, as Bcl-2 and Bcl-XL, and antiapoptotic, as Bcl-X(s), were not modified by FTIs. By contrast, expression of inducible nitric oxide synthase (iNOS) was increased in FTI-treated AML cells. Our results suggest a very complex mechanism of action of FTIs that require more studies for a better clinical use of the drugs alone or in combination in the treatment of hematological malignancies.

No MeSH data available.


Related in: MedlinePlus