The BH3 mimetic drug ABT-737 induces apoptosis and acts synergistically with chemotherapeutic drugs in thyroid carcinoma cells

Abstract

Background:Patients with dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to chemotherapeutic treatment and external irradiation and thus are difficult to treat. Direct induction of apoptosis is a promising approach in these apoptosis-resistant tumor cells. The BH3 mimetic ABT-737 belongs to a new class of drugs that target anti-apoptotic proteins of the BCL-2 family and facilitate cell death. The purpose of this study was to investigate the effect of ABT-737 alone or in combination with chemotherapeutic drugs on thyroid carcinoma cell lines. Methods:A total of 16 cell lines derived from follicular, papillary, and anaplastic thyroid carcinomas were treated with ABT-737. Cell viability was measured with MTT assay. Cell death was determined by cell cycle phase distribution and subG1 peak analyses, determination of caspase 3/7 activity and caspase cleavage products, lactate dehydrogenase (LDH) liberation assays and LC3 analysis by western blot. Results:The number of viable cells was decreased in all cell lines examined after ABT-737 treatment, with IC50 values ranging from 0.73 to 15.6 μM. Biochemical markers of apoptosis like caspase activities, caspase cleavage products and DNA fragmentation determined as SubG1 peak were elevated after ABT-737 treatment, but no LC3 cleavage was induced by ABT-737 indicating no autophagic processes. In combination with doxorubicin and gemcitabine, ABT-737 showed synergistic effects on cell viability. Conclusions:With these experiments we demonstrated the efficacy of the BH3 mimetic drug ABT-737 against dedifferentiated thyroid carcinoma cells of various histological origins and showed synergistic effects with chemotherapeutic drugs. ABT-737-treated cells underwent an apoptotic cell death. ABT-737 and related BH3 mimetic drugs, alone or in combination, may thus be of value as a new therapeutic option for dedifferentiated thyroid carcinomas.

Anticancer activity of diterpenes and steroids from Eunicella singularis against two- and threedimensional breast cancer cell models

“…Induction of apoptosis is one of the active strategies to arrest proliferation of cancer cells. Many chemical agents, such as tamoxifen, exert their anticancer effects by inducing apoptosis and they have been used to treat many types of cancers especially breast cancer [55][56][57]. Thus the anticancer activity observed with all the investigated compounds isolated from the Mediterranean soft coral E. singularis may be related to their prominent apoptotic activity.…”

Bcl‐2 protects TK6 cells against hydroquinone‐induced apoptosis through PARP‐1 cytoplasm translocation and stabilizing mitochondrial membrane potential

“…ABT‐737, a small molecule that occupies the BH3 binding pocket of Bcl‐2, exhibits an antitumor effect on several types of tumors dependent on Bcl‐2 [Kelly et al, ; Broecker‐Preuss et al, ; Roberts et al, ]. Of all the putative BH3 mimetics tested, only ABT‐737 acted similarly to Bcl‐2 by indirectly activating Bax/Bak‐dependent mitochondrial apoptosis [van Delft et al, ].…”

ABT-737 potentiates cisplatin-induced apoptosis in human osteosarcoma cells via the mitochondrial apoptotic pathway

“…ABT-737 is a BH-3 mimetic that interacts and inhibits Bcl-2, and has been previously shown to be an inducer of cancer cell apoptosis (7,8). This mimetic can inhibit the anti-apoptotic Bcl-2 family of proteins (i.e., Bcl-xL, Bcl-2, and Bcl-w), but has a lower effect on Mcl-1 proteins (9,10). Previous research has demonstrated that ABT-737 has a potent single-agent activity or can act synergistically with other chemotherapeutic drugs against various types of hematological malignancies and solid tumors, such as melanoma cells, glioma cells (11), acute myeloid leukemia, chronic lymphocytic leukemia, malignant lymphomas, multiple myelomas, acute lymphoblastic leukemia, and on solid tumors (12).…”

“…Studies from other groups indicate that the mitochondrial apoptotic pathway may be involved in the action of ABT-737 and DDP (19). Apoptosis is composed of two signaling pathways: the extrinsic or death receptor pathway, which is regulated by combining extracellular ligands of the tumor necrosis factor (TNF) family with death receptors, and the intrinsic or mitochondrial pathway, which is controlled by proteins of the B-cell lymphoma (Bcl-2) family (i.e., Bcl-xL, Bcl-w, Mcl-1, Bax, Bak, Bid, Noxa, Puma, and Bim) (9). Interactions and the balance between pro-survival and proapoptotic members could determine the cell's fate (11).…”