Table 7. Bim in Drug-Induced Apoptosis.

Apoptotic Stimulus	Remarks	References
ALK and c-Met inhibitors	• The ALK inhibitor TAE684 induces apoptosis in lung cancer cells through upregulation of Bim and downregulation of survivin. • The dual ALK and c-Met inhibitor Crizotinib induces apoptosis in c-Met-amplificated lung cancer cells and gastric cancer cells through upregulation of Bim. • When combined with EGFR inhibitors, the dual ALK and c-Met inhibitor CM-118 induced apoptosis of c-Met amplified NSCLC cells through Bim upregulation and Mcl-1 downregulation.	[623, 625-627]
BH3 mimetics (e.g., ABT-737, ABT-263 and ABT-199)	• The apoptosis induction of ovarian cancer by ABT-737 was dependent on Bim expression. • ABT-737-mediated release of Bak couldn't induce apoptosis unless Bim associates with oligomeric Bak to promote its conversion to a membrane-inserted pore. • The pro-apoptotic effect of ABT-737 in CLL depends on sufficient amount of Bcl-2 that tonically sequesters the pro-apoptotic Bim protein. • Lung cancer with EGFR mutation and high Bcl-2 expression could be sensitized to cell death by a combination of erlotinib and ABT-737 that was dependent on Bcl-2 primed with Bim. • Primary B-ALL cells expressing high levels of Bcl-2 exhibited great sensitivity to ABT-263 and ABT-199 • BH3 profiling of lymphoma cells identifies cells dependent on Bcl-2 and predicts sensitivity to ABT-737. • Hepatocyte apoptosis induced by ABT-737 was completely prevented in Bim/Bid double knockout mice.	[78, 309, 515, 572, 577, 585, 651]
Bortezomib (Velcade)	• Bortezomib-induced apoptosis of multiple myeloma cells was prevented upon knockdown of Bim. • Bortezomib sensitized prostate cancer cells to TRAIL-induced apoptosis through a mechanism dependent on Bim.	[485, 507]
Etoposide and Doxorubicin	• Etoposide- and doxorubicin-induced apoptosis of neuroblastoma cells was dependent on FoxO3-mediated Bim expression and ROS production that could be prevented by Bcl-xL.	[57]
Flt3 inhibitors	• The Flt3 inhibitors AG1295 and PKC412 induced apoptosis of acute myeloid leumemia cells that was dependent on FoxO3a-mediated Bim induction and inactivation of the PI3K/Akt pathway.	[652]
Glucocorticoids	• Glucocorticoid-induced apoptosis of thymocytes, T and B acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma and thymoma cells depends on Bim. • Glucocorticoid-induced apoptosis of osteoblasts and insulin-producing β-cells is mediated by Bim. • Glucocorticoid-induced Bim expression is mediated by FoxO3, c-Jun and Runx1, and promoted by p38 MAPK signaling. • Glucocorticoid-mediated apoptosis of thymocytes and lymphoid malignancies depends on GSK3 and resistance is often caused by PI3K/Akt-mediated inhibition of GSK3. • GSK3 interacts with Bim following glucocorticoid treatment of thymocytes and lymphoid malignancies.	[14, 21, 49, 63, 158, 341, 458, 517-521, 523, 653]
Histone deacetylase (HDAC) inhibitors	• The HDAC inhibitor suberic bishydroxamate (SBHA) upregulated Bim, Bax and Bak in human melanoma cells. • The HDAC inhibitor Trichostatin A restored histone acetylation, with concomitant upregulation of Bim. • Trichostatin A suppressed miR-106b∼93∼25 expression through downregulation of c-Myc, thereby increasing Bim expression and apoptosis in human endometrial cancer cells. • The HDAC inhibitor vorinostat increased Bim expression and sensitized EGFR-mutant non-small-cell lung cancer (NSCLC) to the tyrosine kinase inhibitor gefitinib.	[32, 242, 245, 272, 503, 539]
Imatinib (STI571)-induced apoptosis	• Bim expression is downregulated in Bcr-Abl+ leukemia cells. • STI571 increases FoxO3a-dependent transcription of Bim, which was shown to be important for apoptosis. • Imatinib induces the expression of hypophosphorylated BimEL in K562 and BV173 chronic myelogenic leukemia cells. • Bim knockdown reduced susceptibility to imatinib-induced apoptosis. • Imatinib induces apoptosis of c-Kit-dependent gastrointestinal stromal tumor cells.	[121, 248, 249, 304, 305, 501, 549, 646]
Erlotinib-induced apoptosis	• The EGFR kinase inhibitor Erlotinib increased Bim expression in lung cancer cells sensitive to the drug, but not in resistant cells. • Bcl-2 inhibits the cell death induced by erlotinib.	[308, 309]
Gefitinib-induced apoptosis	• Bim is involved in gefitinib-induced apoptosis in sensitive EGFR-mutant cancer cells. • T790M mutation in EGFR prevented gefitinib-induced upregulation of Bim and apoptosis. • T790M mutated cells responded with Bim upregulation and apoptosis when using the irreversible tyrosine kinase inhibitor CL-387,785.	[306, 307]
Lapatinib-induced apoptosis	• Lapatinib treatment of sensitive, but not resistant, HER2+ breast cancer cells led to increased Bim expression. • Downregulation of PTK6 induced apoptosis of resistant breast cancer cells through a Bim-dependent mechanism.	[500]
Mutant B-RafV600E inhibitor-induced apoptosis	• Inhibition of B-RafV600E in melanoma cells by PLX4720 led to induction of the three Bim isoforms BimEL, BimL, and BimS, but the increase in BimS was the most profound. • The splicing factor SRp55 was responsible for the increased BimS splicing. • Dual treatment of PTEN-negative melanoma cells with PLX4720 and a PI3K inhibitor enhanced Bim expression and apoptosis. • Combining the B-Raf inhibitor vemurafenib with the MEK inhibitor trametinib increased Bim expression and apoptosis.	[235, 541, 633]
Paclitaxel (Taxol)-induced apoptosis	• Paclitaxel induced FoxO3a and Bim expression in MCF-7 cells, both involved in apoptosis. • Knockdown of Bim decreased the susceptibility of non-small-cell lung cancer (NSCLC) cells to paclitaxel-mediated killing. • siRNA silencing of Bim reduced sensitivity of K562 cells to Taxol-induced cell death.	[118, 346, 482, 654, 655]
PP2A activator	• The PP2A activator FTY720 induces apoptosis of chronic myelogenic leukemia cells through activation of Bim and Bid. • FTY720 overcomes tyrosine kinase inhibitor resistance caused by Abl kinase domain mutations.	[656]