Cytotoxic Marine Alkaloid 3,10-Dibromofascaplysin Induces Apoptosis and Synergizes with Cytarabine Resulting in Leukemia Cell Death

TY - JOUR

T1 - Cytotoxic Marine Alkaloid 3,10-Dibromofascaplysin Induces Apoptosis and Synergizes with Cytarabine Resulting in Leukemia Cell Death

AU - Spirin, Pavel

AU - Shyrokova, Elena

AU - Lebedev, Timofey

AU - Vagapova, Elmira

AU - Smirnova, Polina

AU - Kantemirov, Alexey

AU - Dyshlovoy, Sergey A

AU - Amsberg, Gunhild von

AU - Zhidkov, Maxim

AU - Prassolov, Vladimir

PY - 2021/8/27

Y1 - 2021/8/27

N2 - Myeloid leukemia is a hematologic neoplasia characterized by a clonal proliferation of hematopoietic stem cell progenitors. Patient prognosis varies depending on the subtype of leukemia as well as eligibility for intensive treatment regimens and allogeneic stem cell transplantation. Although significant progress has been made in the therapy of patients including novel targeted treatment approaches, there is still an urgent need to optimize treatment outcome. The most common therapy is based on the use of chemotherapeutics cytarabine and anthrayclines. Here, we studied the effect of the recently synthesized marine alkaloid 3,10-dibromofascaplysin (DBF) in myeloid leukemia cells. Unsubstituted fascaplysin was early found to affect cell cycle via inhibiting CDK4/6, thus we compared the activity of DBF and other brominated derivatives with known CDK4/6 inhibitor palbociclib, which was earlier shown to be a promising candidate to treat leukemia. Unexpectedly, the effect DBF on cell cycle differs from palbociclib. In fact, DBF induced leukemic cells apoptosis and decreased the expression of genes responsible for cancer cell survival. Simultaneously, DBF was found to activate the E2F1 transcription factor. Using bioinformatical approaches we evaluated the possible molecular mechanisms, which may be associated with DBF-induced activation of E2F1. Finally, we found that DBF synergistically increase the cytotoxic effect of cytarabine in different myeloid leukemia cell lines. In conclusion, DBF is a promising drug candidate, which may be used in combinational therapeutics approaches to reduce leukemia cell growth.

AB - Myeloid leukemia is a hematologic neoplasia characterized by a clonal proliferation of hematopoietic stem cell progenitors. Patient prognosis varies depending on the subtype of leukemia as well as eligibility for intensive treatment regimens and allogeneic stem cell transplantation. Although significant progress has been made in the therapy of patients including novel targeted treatment approaches, there is still an urgent need to optimize treatment outcome. The most common therapy is based on the use of chemotherapeutics cytarabine and anthrayclines. Here, we studied the effect of the recently synthesized marine alkaloid 3,10-dibromofascaplysin (DBF) in myeloid leukemia cells. Unsubstituted fascaplysin was early found to affect cell cycle via inhibiting CDK4/6, thus we compared the activity of DBF and other brominated derivatives with known CDK4/6 inhibitor palbociclib, which was earlier shown to be a promising candidate to treat leukemia. Unexpectedly, the effect DBF on cell cycle differs from palbociclib. In fact, DBF induced leukemic cells apoptosis and decreased the expression of genes responsible for cancer cell survival. Simultaneously, DBF was found to activate the E2F1 transcription factor. Using bioinformatical approaches we evaluated the possible molecular mechanisms, which may be associated with DBF-induced activation of E2F1. Finally, we found that DBF synergistically increase the cytotoxic effect of cytarabine in different myeloid leukemia cell lines. In conclusion, DBF is a promising drug candidate, which may be used in combinational therapeutics approaches to reduce leukemia cell growth.

KW - Antineoplastic Agents/pharmacology

KW - Cell Line, Tumor

KW - Cell Physiological Phenomena/drug effects

KW - Cytarabine/pharmacology

KW - Drug Synergism

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Leukemia, Myeloid/drug therapy

KW - Oxindoles/pharmacology

U2 - 10.3390/md19090489

DO - 10.3390/md19090489

M3 - SCORING: Journal article

C2 - 34564151

VL - 19

JO - MAR DRUGS

JF - MAR DRUGS

SN - 1660-3397

IS - 9

M1 - 486

ER -