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Marine benthic cyanobacteria contain apoptosis-inducing activity synergizing with daunorubicin to kill leukemia cells, but not cardiomyocytes.

Oftedal L, Selheim F, Wahlsten M, Sivonen K, Døskeland SO, Herfindal L - Mar Drugs (2010)

Bottom Line: The apoptotic cell death induced by the various strains could be distinguished by the role of caspase activation and sensitivity to the recently detected chemotherapy-resistance-associated prosurvival protein LEDGF/p75.One strain (M44) was particularly promising since its activity counteracted the protective effect of LEDGF/p75 overexpressed in AML cells, acted synergistically with the anthracycline anticancer drug daunorubicin in AML cells, and protected cardiomyoblasts against the toxic effect of anthracyclines.We conclude that culturable benthic marine cyanobacteria from temperate environments provide a promising and hitherto underexploited source for novel antileukemic drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. linn.oftedal@biomed.uib.no

ABSTRACT
The potential of marine benthic cyanobacteria as a source of anticancer drug candidates was assessed in a screen for induction of cell death (apoptosis) in acute myeloid leukemia (AML) cells. Of the 41 marine cyanobacterial strains screened, more than half contained cell death-inducing activity. Several strains contained activity against AML cells, but not against non-malignant cells like hepatocytes and cardiomyoblasts. The apoptotic cell death induced by the various strains could be distinguished by the role of caspase activation and sensitivity to the recently detected chemotherapy-resistance-associated prosurvival protein LEDGF/p75. One strain (M44) was particularly promising since its activity counteracted the protective effect of LEDGF/p75 overexpressed in AML cells, acted synergistically with the anthracycline anticancer drug daunorubicin in AML cells, and protected cardiomyoblasts against the toxic effect of anthracyclines. We conclude that culturable benthic marine cyanobacteria from temperate environments provide a promising and hitherto underexploited source for novel antileukemic drugs.

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Cyanobacterial extracts induced rapid apoptosis in HL-60 acute myeloid leukemia cells. HL-60 cells were incubated without (Ctr) or with 4 mg DW biomass/mL of aqueous cyanobacterial extracts for 30, 60 or 120 min. Cells were fixed and stained, and apoptosis assessed as described in the legend to Figure 1. The results are mean and SEM, n = 3.
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f3-marinedrugs-08-02659: Cyanobacterial extracts induced rapid apoptosis in HL-60 acute myeloid leukemia cells. HL-60 cells were incubated without (Ctr) or with 4 mg DW biomass/mL of aqueous cyanobacterial extracts for 30, 60 or 120 min. Cells were fixed and stained, and apoptosis assessed as described in the legend to Figure 1. The results are mean and SEM, n = 3.

Mentions: Although the IPC-81 AML cells used in the primary screen respond in a clinically relevant way to present day anti-leukemic drugs both in vivo and in vitro [23,27], it is important to know if the IPC-81 apoptogens induce death in other relevant AML cell lines. In this respect, the aqueous extracts from M27, M30 and M44 were overall more efficient than those from M45 and M4 (not shown). M27, M30 and M44 induced apoptosis rapidly in human HL-60 AML cells (Figure 3), even compared to a higher-than-therapeutic concentration of daunorubicin in these cells ([27], data not shown). The high potency and rapid action of M27, M30 and M44 towards the leukemia cells are advantageous for in vivo therapy, since there will be a shorter burst of the drug, thus allowing less time for the formation of potentially generally harmful metabolites of the drug. For these reasons, the aqueous extracts from M27, M30 and M44 were selected for further studies.


Marine benthic cyanobacteria contain apoptosis-inducing activity synergizing with daunorubicin to kill leukemia cells, but not cardiomyocytes.

Oftedal L, Selheim F, Wahlsten M, Sivonen K, Døskeland SO, Herfindal L - Mar Drugs (2010)

Cyanobacterial extracts induced rapid apoptosis in HL-60 acute myeloid leukemia cells. HL-60 cells were incubated without (Ctr) or with 4 mg DW biomass/mL of aqueous cyanobacterial extracts for 30, 60 or 120 min. Cells were fixed and stained, and apoptosis assessed as described in the legend to Figure 1. The results are mean and SEM, n = 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2992999&req=5

f3-marinedrugs-08-02659: Cyanobacterial extracts induced rapid apoptosis in HL-60 acute myeloid leukemia cells. HL-60 cells were incubated without (Ctr) or with 4 mg DW biomass/mL of aqueous cyanobacterial extracts for 30, 60 or 120 min. Cells were fixed and stained, and apoptosis assessed as described in the legend to Figure 1. The results are mean and SEM, n = 3.
Mentions: Although the IPC-81 AML cells used in the primary screen respond in a clinically relevant way to present day anti-leukemic drugs both in vivo and in vitro [23,27], it is important to know if the IPC-81 apoptogens induce death in other relevant AML cell lines. In this respect, the aqueous extracts from M27, M30 and M44 were overall more efficient than those from M45 and M4 (not shown). M27, M30 and M44 induced apoptosis rapidly in human HL-60 AML cells (Figure 3), even compared to a higher-than-therapeutic concentration of daunorubicin in these cells ([27], data not shown). The high potency and rapid action of M27, M30 and M44 towards the leukemia cells are advantageous for in vivo therapy, since there will be a shorter burst of the drug, thus allowing less time for the formation of potentially generally harmful metabolites of the drug. For these reasons, the aqueous extracts from M27, M30 and M44 were selected for further studies.

Bottom Line: The apoptotic cell death induced by the various strains could be distinguished by the role of caspase activation and sensitivity to the recently detected chemotherapy-resistance-associated prosurvival protein LEDGF/p75.One strain (M44) was particularly promising since its activity counteracted the protective effect of LEDGF/p75 overexpressed in AML cells, acted synergistically with the anthracycline anticancer drug daunorubicin in AML cells, and protected cardiomyoblasts against the toxic effect of anthracyclines.We conclude that culturable benthic marine cyanobacteria from temperate environments provide a promising and hitherto underexploited source for novel antileukemic drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. linn.oftedal@biomed.uib.no

ABSTRACT
The potential of marine benthic cyanobacteria as a source of anticancer drug candidates was assessed in a screen for induction of cell death (apoptosis) in acute myeloid leukemia (AML) cells. Of the 41 marine cyanobacterial strains screened, more than half contained cell death-inducing activity. Several strains contained activity against AML cells, but not against non-malignant cells like hepatocytes and cardiomyoblasts. The apoptotic cell death induced by the various strains could be distinguished by the role of caspase activation and sensitivity to the recently detected chemotherapy-resistance-associated prosurvival protein LEDGF/p75. One strain (M44) was particularly promising since its activity counteracted the protective effect of LEDGF/p75 overexpressed in AML cells, acted synergistically with the anthracycline anticancer drug daunorubicin in AML cells, and protected cardiomyoblasts against the toxic effect of anthracyclines. We conclude that culturable benthic marine cyanobacteria from temperate environments provide a promising and hitherto underexploited source for novel antileukemic drugs.

Show MeSH
Related in: MedlinePlus