Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells View Full Text


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Article Info

DATE

2018-12-20

AUTHORS

Rogério Bodini Benati, Tássia Rafaela Costa, Maira da Costa Cacemiro, Suely Vilela Sampaio, Fabíola Attié de Castro, Sandra Mara Burin

ABSTRACT

BackgroundChronic myeloid leukemia (CML) is a BCR-ABL1+ myeloproliferative neoplasm marked by increased myeloproliferation and presence of leukemic cells resistant to apoptosis. The current first-line therapy for CML is administration of the tyrosine kinase inhibitors imatinib mesylate, dasatinib or nilotinib. Although effective to treat CML, some patients have become resistant to this therapy, leading to disease progression and death. Thus, the discovery of new compounds to improve CML therapy is still challenging. Here we addressed whether MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, affects the viability of imatinib mesylate-resistant Bcr-Abl+ cell lines.MethodsWe examined the cytotoxic and pro-apoptotic effect of MjTX-I in K562-S and K562-R Bcr-Abl+ cells and in the non-tumor HEK-293 cell line and peripheral blood mononuclear cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and the hypotonic fluorescent solution methods, associated with detection of caspases 3, 8, and 9 activation and poly (ADP-ribose) polymerase (PARP) cleavage. We also analyzed the MjTX-I potential to modulate the expression of apoptosis-related genes in K562-S and K562-R cells.ResultsMjTX-I decreased the viability of K562-S and K562-R cells by 60 to 65%, without affecting the viability of the non-tumor cells, i.e. it exerted selective cytotoxicity towards Bcr-Abl+ cell lines. In leukemic cell lines, the toxin induced apoptosis, activated caspases 3, 8, and 9, cleaved PARP, downregulated expression of the anti-apoptotic gene BCL-2, and upregulated expression of the pro-apoptotic gene BAD.ConclusionThe antitumor effect of MjTX-I is associated with its potential to induce apoptosis and cytotoxicity in Bcr-Abl positive cell lines sensitive and resistant to imatinib mesylate, indicating that MjTX-I is a promising candidate drug to upgrade the CML therapy. More... »

PAGES

40

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s40409-018-0180-9

    DOI

    http://dx.doi.org/10.1186/s40409-018-0180-9

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    22 schema:description BackgroundChronic myeloid leukemia (CML) is a BCR-ABL1+ myeloproliferative neoplasm marked by increased myeloproliferation and presence of leukemic cells resistant to apoptosis. The current first-line therapy for CML is administration of the tyrosine kinase inhibitors imatinib mesylate, dasatinib or nilotinib. Although effective to treat CML, some patients have become resistant to this therapy, leading to disease progression and death. Thus, the discovery of new compounds to improve CML therapy is still challenging. Here we addressed whether MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, affects the viability of imatinib mesylate-resistant Bcr-Abl+ cell lines.MethodsWe examined the cytotoxic and pro-apoptotic effect of MjTX-I in K562-S and K562-R Bcr-Abl+ cells and in the non-tumor HEK-293 cell line and peripheral blood mononuclear cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and the hypotonic fluorescent solution methods, associated with detection of caspases 3, 8, and 9 activation and poly (ADP-ribose) polymerase (PARP) cleavage. We also analyzed the MjTX-I potential to modulate the expression of apoptosis-related genes in K562-S and K562-R cells.ResultsMjTX-I decreased the viability of K562-S and K562-R cells by 60 to 65%, without affecting the viability of the non-tumor cells, i.e. it exerted selective cytotoxicity towards Bcr-Abl+ cell lines. In leukemic cell lines, the toxin induced apoptosis, activated caspases 3, 8, and 9, cleaved PARP, downregulated expression of the anti-apoptotic gene BCL-2, and upregulated expression of the pro-apoptotic gene BAD.ConclusionThe antitumor effect of MjTX-I is associated with its potential to induce apoptosis and cytotoxicity in Bcr-Abl positive cell lines sensitive and resistant to imatinib mesylate, indicating that MjTX-I is a promising candidate drug to upgrade the CML therapy.
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    29 BCR
    30 BCR-ABL positive cell lines
    31 BCR-ABL1
    32 BackgroundChronic myeloid leukemia
    33 Bcl-2
    34 Bothrops moojeni snake venom
    35 CML
    36 CML therapy
    37 HEK-293 cell line
    38 K562
    39 MethodsWe
    40 MjTX
    41 PARP
    42 action
    43 activation
    44 administration
    45 anti-apoptotic gene Bcl-2
    46 antitumor effects
    47 apoptosis
    48 apoptosis-related genes
    49 blood mononuclear cells
    50 bromide
    51 candidate drugs
    52 caspase-3
    53 cell lines
    54 cells
    55 cleavage
    56 compounds
    57 current first-line therapy
    58 cytotoxic
    59 cytotoxicity
    60 dasatinib
    61 death
    62 detection
    63 dimethylthiazol-2
    64 diphenyltetrazolium bromide
    65 discovery
    66 downregulated expression
    67 drugs
    68 effect
    69 expression
    70 first-line therapy
    71 gene Bcl-2
    72 genes
    73 inhibitors
    74 kinase inhibitors
    75 leukemia
    76 leukemic cell lines
    77 leukemic cells
    78 lines
    79 mesylate
    80 method
    81 mononuclear cells
    82 myeloid leukemia
    83 myeloproliferation
    84 myeloproliferative neoplasms
    85 neoplasms
    86 new compounds
    87 nilotinib
    88 non-tumor cells
    89 patients
    90 peripheral blood mononuclear cells
    91 phospholipase A2
    92 poly (ADP-ribose) polymerase cleavage
    93 polymerase cleavage
    94 positive cell lines
    95 potential
    96 presence
    97 pro-apoptotic action
    98 pro-apoptotic effects
    99 pro-apoptotic genes
    100 progression
    101 promising candidate drug
    102 selective cytotoxicity
    103 snake venom
    104 solution method
    105 therapy
    106 toxin
    107 tyrosine kinase inhibitors
    108 upregulated expression
    109 venom
    110 viability
    111 viability of K562
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