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Akacid medical formulation induces apoptosis in myeloid and lymphatic leukemic cell lines in vitro and in vivo.

Neuwirt H, Wabnig E, Feistritzer C, Eder IE, Salvador C, Puhr M, Culig Z, Massoner P, Tiefenthaler M, Steurer M, Konwalinka G - PLoS ONE (2015)

Bottom Line: We have previously shown that AMF exerts antiproliferative effects on a variety of solid tumor cell lines.This effect was found also in G0-arrested cells.Finally, in our animal experiments utilizing male nu/nu Balb/c mice we found a significant growth retardation, which was immunohistochemically associated with a significantly lower number of KI67-positive cells and caspase-3 induction in AMF-treated mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine IV, Medical University of Innsbruck, Innsbruck, Austria.

ABSTRACT
Akacid medical formulation (AMF) is an oligoguanidine that exerts biocidal activity against airborne and surface microorganisms including bacteria, viruses, fungi, and molds, while showing relatively low toxicity to humans. We have previously shown that AMF exerts antiproliferative effects on a variety of solid tumor cell lines. In this study we raised the question whether AMF could also substantially inhibit cell growth or induce apoptosis in cell lines derived from hematologic malignancies such as leukemia or lymphoma. We found that AMF has antiproliferative effects on various hematologic cell lines derived from human leukemia and lymphoma. Additionally, we show that AMF induces apoptosis in leukemia cell lines not only via the extrinsic and intrinsic pathway, but also in a caspase-independent manner. This effect was found also in G0-arrested cells. Finally, in our animal experiments utilizing male nu/nu Balb/c mice we found a significant growth retardation, which was immunohistochemically associated with a significantly lower number of KI67-positive cells and caspase-3 induction in AMF-treated mice.

No MeSH data available.


Related in: MedlinePlus

Apoptosis is also induced in presence of a pan-caspase inhibitor.Cells were preincubated with Z-VAD-fmk, a pan-caspase inhibitor, before AMF treatment and apoptosis induction was assessed using Annexin-V and propidiumiodide staining and flow cytometry. n = 4 (number of independent experiments carried out in triplicates).
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pone.0117806.g005: Apoptosis is also induced in presence of a pan-caspase inhibitor.Cells were preincubated with Z-VAD-fmk, a pan-caspase inhibitor, before AMF treatment and apoptosis induction was assessed using Annexin-V and propidiumiodide staining and flow cytometry. n = 4 (number of independent experiments carried out in triplicates).

Mentions: Next we raised the question if AMF-induced apoptosis was only associated with activation of caspases or causally linked to it. To answer this question, we pretreated HL-60 and CEM C7H2 cells with 20 μM of the pan-caspase inhibitor Z-VAD-fmk before addition of AMF and AV/PI labeling. In order the test the cellular system, a FAS-ligand (FASL) control was also included, as it has been shown that Z-VAD-fmk significantly inhibits FASL-induced apoptosis (see S1 Fig.). After 24 and 48 hours of AMF treatment (10–30 μM), preincubation with pan-caspase inhibitor did not significantly reduce induction of apoptosis in neither of the two cell lines tested (Fig. 5). These results strongly suggest that AMF-induced apoptosis does not depend only on caspase activation. Similar results have been shown in various cell lines using, for example, magnolol (a small-molecule hydroxylated biphenol) [17], alpha hydroxy acid [18] and distillation remnants from Japanese liquor [19]. Additionally, it has been shown that chemotherapeutics like topoisomerase II inhibitors, kinase inhibitors and proteasome inhibitors may induce apoptosis also by a caspase independent pathway possibly depending on Panx1 expression, which is a structural component in gap junctions and hemichannels an involved in nucleotide release during chemotherapeutic-drug induced apoptosis [20]. Matsumoto et al. also reported of a small-molecule inhibitor of glioma-associated oncogene 1 and -2 treatment induced caspase-independent apoptosis in a Ewing´s sarcoma cell line, which was associated with decreased expression of survivin, cyclin A and increase of p21 [21]. Another study published by Wang et al. showed that a citrus 5-acetyl-tetramethoxyflavone induces apoptosis in breast cancer cells via both caspase-dependent and –independent pathways, the latter being mediated by translocation of apoptosis inducing factor (AIF) into the nucleus [22,23]. Similar results have been reported in glioma cells after tetrandrine (a bis-benzylisoquinoline alkaloid) treatment [24]. Cordycepol C, a sesquiterpene isolated from a fungus species named cordyceps ophioglossoides, induced caspase-independent apoptosis in human hepatocellular carcinoma cells [25]. Similarly, Ashour et al. found that Rottlerin, a polyphenole isolated from Kamala trees, induced caspase-independent apoptosis [26]. The proposed mechanism of apoptosis induction by Cordycepol C and Rottlerin again was nuclear translocation of AIF.


Akacid medical formulation induces apoptosis in myeloid and lymphatic leukemic cell lines in vitro and in vivo.

Neuwirt H, Wabnig E, Feistritzer C, Eder IE, Salvador C, Puhr M, Culig Z, Massoner P, Tiefenthaler M, Steurer M, Konwalinka G - PLoS ONE (2015)

Apoptosis is also induced in presence of a pan-caspase inhibitor.Cells were preincubated with Z-VAD-fmk, a pan-caspase inhibitor, before AMF treatment and apoptosis induction was assessed using Annexin-V and propidiumiodide staining and flow cytometry. n = 4 (number of independent experiments carried out in triplicates).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4334520&req=5

pone.0117806.g005: Apoptosis is also induced in presence of a pan-caspase inhibitor.Cells were preincubated with Z-VAD-fmk, a pan-caspase inhibitor, before AMF treatment and apoptosis induction was assessed using Annexin-V and propidiumiodide staining and flow cytometry. n = 4 (number of independent experiments carried out in triplicates).
Mentions: Next we raised the question if AMF-induced apoptosis was only associated with activation of caspases or causally linked to it. To answer this question, we pretreated HL-60 and CEM C7H2 cells with 20 μM of the pan-caspase inhibitor Z-VAD-fmk before addition of AMF and AV/PI labeling. In order the test the cellular system, a FAS-ligand (FASL) control was also included, as it has been shown that Z-VAD-fmk significantly inhibits FASL-induced apoptosis (see S1 Fig.). After 24 and 48 hours of AMF treatment (10–30 μM), preincubation with pan-caspase inhibitor did not significantly reduce induction of apoptosis in neither of the two cell lines tested (Fig. 5). These results strongly suggest that AMF-induced apoptosis does not depend only on caspase activation. Similar results have been shown in various cell lines using, for example, magnolol (a small-molecule hydroxylated biphenol) [17], alpha hydroxy acid [18] and distillation remnants from Japanese liquor [19]. Additionally, it has been shown that chemotherapeutics like topoisomerase II inhibitors, kinase inhibitors and proteasome inhibitors may induce apoptosis also by a caspase independent pathway possibly depending on Panx1 expression, which is a structural component in gap junctions and hemichannels an involved in nucleotide release during chemotherapeutic-drug induced apoptosis [20]. Matsumoto et al. also reported of a small-molecule inhibitor of glioma-associated oncogene 1 and -2 treatment induced caspase-independent apoptosis in a Ewing´s sarcoma cell line, which was associated with decreased expression of survivin, cyclin A and increase of p21 [21]. Another study published by Wang et al. showed that a citrus 5-acetyl-tetramethoxyflavone induces apoptosis in breast cancer cells via both caspase-dependent and –independent pathways, the latter being mediated by translocation of apoptosis inducing factor (AIF) into the nucleus [22,23]. Similar results have been reported in glioma cells after tetrandrine (a bis-benzylisoquinoline alkaloid) treatment [24]. Cordycepol C, a sesquiterpene isolated from a fungus species named cordyceps ophioglossoides, induced caspase-independent apoptosis in human hepatocellular carcinoma cells [25]. Similarly, Ashour et al. found that Rottlerin, a polyphenole isolated from Kamala trees, induced caspase-independent apoptosis [26]. The proposed mechanism of apoptosis induction by Cordycepol C and Rottlerin again was nuclear translocation of AIF.

Bottom Line: We have previously shown that AMF exerts antiproliferative effects on a variety of solid tumor cell lines.This effect was found also in G0-arrested cells.Finally, in our animal experiments utilizing male nu/nu Balb/c mice we found a significant growth retardation, which was immunohistochemically associated with a significantly lower number of KI67-positive cells and caspase-3 induction in AMF-treated mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine IV, Medical University of Innsbruck, Innsbruck, Austria.

ABSTRACT
Akacid medical formulation (AMF) is an oligoguanidine that exerts biocidal activity against airborne and surface microorganisms including bacteria, viruses, fungi, and molds, while showing relatively low toxicity to humans. We have previously shown that AMF exerts antiproliferative effects on a variety of solid tumor cell lines. In this study we raised the question whether AMF could also substantially inhibit cell growth or induce apoptosis in cell lines derived from hematologic malignancies such as leukemia or lymphoma. We found that AMF has antiproliferative effects on various hematologic cell lines derived from human leukemia and lymphoma. Additionally, we show that AMF induces apoptosis in leukemia cell lines not only via the extrinsic and intrinsic pathway, but also in a caspase-independent manner. This effect was found also in G0-arrested cells. Finally, in our animal experiments utilizing male nu/nu Balb/c mice we found a significant growth retardation, which was immunohistochemically associated with a significantly lower number of KI67-positive cells and caspase-3 induction in AMF-treated mice.

No MeSH data available.


Related in: MedlinePlus