TY - JOUR
T1 - BCL-xL-selective BH3 mimetic sensitizes rhabdomyosarcoma cells to chemotherapeutics by activation of the mitochondrial pathway of apoptosis
AU - Faqar-Uz-Zaman, Sara Fatima
AU - Heinicke, Ulrike
AU - Meister, Michael Torsten
AU - Vogler, Meike
AU - Fulda, Simone
N1 - Copyright © 2017 Elsevier B.V. All rights reserved.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - BH3 mimetics are a promising new class of anticancer agents that inhibit antiapoptotic BCL-2 proteins. Here, we report that BH3 mimetics selectively targeting BCL-xL, BCL-2 or MCL-1 (i.e. A-1331852, ABT-199, A-1210477) act in concert with multiple chemotherapeutic agents (i.e. vincristine (VCR), etoposide (ETO), doxorubicin, actinomycin D and cyclophosphamide) to induce apoptosis in rhabdomyosarcoma (RMS) cells. Similarly, genetic knockdown of BCL-xL primes RMS cells to VCR- or ETO-induced cell death, highlighting the importance of BCL-xL in mediating chemotherapy resistance in RMS. A-1331852 and VCR or ETO cooperate to stimulate caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor zVAD.fmk rescues cells from cell death. Molecular studies reveal that VCR/A-1331852 co-treatment causes profound mitotic arrest, which initiates phosphorylation of BCL-2, thereby promoting its inactivation. Also, A-1331852 and VCR or ETO act together to trigger BAX and BAK activation, followed by loss of mitochondrial membrane potential (MMP). Consistently, overexpression of BCL-2 or MCL-1 markedly reduces VCR/A-1331852- or ETO/A-1331852-mediated apoptosis, underscoring that mitochondrial apoptosis represents a key event in synergistic drug interaction. In conclusion, our findings provide a rationale for the combination of BH3 mimetics with conventional chemotherapeutic agents to increase the chemosensitivity of RMS.
AB - BH3 mimetics are a promising new class of anticancer agents that inhibit antiapoptotic BCL-2 proteins. Here, we report that BH3 mimetics selectively targeting BCL-xL, BCL-2 or MCL-1 (i.e. A-1331852, ABT-199, A-1210477) act in concert with multiple chemotherapeutic agents (i.e. vincristine (VCR), etoposide (ETO), doxorubicin, actinomycin D and cyclophosphamide) to induce apoptosis in rhabdomyosarcoma (RMS) cells. Similarly, genetic knockdown of BCL-xL primes RMS cells to VCR- or ETO-induced cell death, highlighting the importance of BCL-xL in mediating chemotherapy resistance in RMS. A-1331852 and VCR or ETO cooperate to stimulate caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor zVAD.fmk rescues cells from cell death. Molecular studies reveal that VCR/A-1331852 co-treatment causes profound mitotic arrest, which initiates phosphorylation of BCL-2, thereby promoting its inactivation. Also, A-1331852 and VCR or ETO act together to trigger BAX and BAK activation, followed by loss of mitochondrial membrane potential (MMP). Consistently, overexpression of BCL-2 or MCL-1 markedly reduces VCR/A-1331852- or ETO/A-1331852-mediated apoptosis, underscoring that mitochondrial apoptosis represents a key event in synergistic drug interaction. In conclusion, our findings provide a rationale for the combination of BH3 mimetics with conventional chemotherapeutic agents to increase the chemosensitivity of RMS.
KW - Antineoplastic Agents/pharmacology
KW - Apoptosis/drug effects
KW - Benzothiazoles/pharmacology
KW - Cell Line, Tumor
KW - Etoposide/pharmacology
KW - Humans
KW - Isoquinolines/pharmacology
KW - Mitochondria/drug effects
KW - Rhabdomyosarcoma/drug therapy
KW - Vincristine/pharmacology
KW - bcl-2-Associated X Protein/physiology
KW - bcl-X Protein/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85032673226&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2017.09.025
DO - 10.1016/j.canlet.2017.09.025
M3 - Article
C2 - 28947136
SN - 1872-7980
VL - 412
SP - 131
EP - 142
JO - Cancer Letters
JF - Cancer Letters
ER -