meayamycin and Lung-Neoplasms

The myeloid cell leukemia-1 (MCL1) gene encodes antiapoptotic Mcl-1(L) and proapoptotic Mcl-1(S) proteins. In cancer, the Mcl-1(L)/Mcl-1(S) ratio is very high, accounting for the antiapoptotic nature of cancer cells. As such, reducing this ratio can render the cancer cells prone to apoptosis. The Mcl-1(L)/Mcl-1(S) ratio is determined in the alternative pre-mRNA splicing step that is regulated by splicing factor 3B1 (SF3B1). Here, we report that meayamycin B, a potent inhibitor of SF3B1, reversed the dominant isoform from Mcl-1(L) to Mcl-1(S) at the mRNA and protein levels. The resulting proapoptotic cellular environment was further exploited; when meayamycin B was combined with Bcl-x(L) inhibitor ABT-737, the combination treatment triggered apoptosis in nonsmall cell lung cancer A549 and H1299 cells that were otherwise resistant to ABT-737. These results demonstrate that perturbation of the MCL1 splicing with small molecule inhibitors of SF3B1 provides a means to sensitize cancer cells toward Bcl-x(L) inhibitors.

Topics: Alternative Splicing; Apoptosis; bcl-X Protein; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; Epoxy Compounds; Humans; Lung Neoplasms; Morpholines; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Phosphoproteins; Piperazines; Protein Isoforms; Pyrans; Ribonucleoprotein, U2 Small Nuclear; RNA Splicing Factors; Sulfonamides

FR901464 is a potent antitumor natural product that binds to the splicing factor 3b complex and inhibits pre-mRNA splicing. Its analogue, meayamycin, is two orders of magnitude more potent as an antiproliferative agent against human breast cancer MCF-7 cells. Here, we report the picomolar antiproliferative activity of meayamycin against various cancer cell lines and multidrug-resistant cells. Time-dependence studies implied that meayamycin may form a covalent bond with its target protein(s). Meayamycin inhibited pre-mRNA splicing in HEK-293 cells but not alternative splicing in a neuronal system. Meayamycin exhibited specificity toward human lung cancer cells compared with nontumorigenic human lung fibroblasts and retained picomolar growth-inhibitory activity against multidrug-resistant cells. These data suggest that meayamycin is a useful chemical probe to study pre-mRNA splicing in live cells and is a promising lead as an anticancer agent.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Drug Resistance, Neoplasm; Epoxy Compounds; Humans; Lung Neoplasms; Pyrans; RNA Precursors; RNA Splicing; RNA, Messenger; Spiro Compounds