A Novel Target Molecule Therapy for Breast Cancer using Tetrocarcin A(TC-A)

失去生长控制和内在的凋亡抑制物可能通过促进突变和促进对各种治疗的耐药性来促进癌症的生存。与此同时，针对肿瘤的靶向分子治疗已被广泛接受，并开发了各种靶向分子治疗剂。Bcl2和Bclxl蛋白是Bcl2家族的成员，已被证明对某些形式的细胞凋亡具有保护作用。此外，这些分子的过度表达被认为通过抗凋亡作用促进了恶性细胞的扩张。另一方面，通过多种方法从大斑小单孢菌KY11091的发酵液中分离得到一种新型的抗肿瘤抗生素。最近，TC-A在T细胞系中被证实是抗凋亡分子Bcl2和/或Bclxl的抑制因子，并通过线粒体途径促进细胞凋亡。在这里，我们检测了TC-A对人乳腺癌细胞如MDA-231、ZR75-1和KPL-1过表达的Bcl2和/或Bclxl的影响。低浓度(2.5μM)的TC-A通过线粒体途径诱导这些细胞发生典型的凋亡。然而，Western blotting分析显示，这些分子的表达没有受到任何影响。综上所述，抗菌药物TC-A可能是一种新的诱导人乳腺癌Bcl2和/或Bclxl过表达的细胞凋亡的药物，但其确切机制尚不清楚。基于这些结果，TC-A将成为一种治疗化疗耐药的乳腺癌的新型化疗药物。我们在2003年和2004年日本外科学会年会和2004年日本乳腺癌学会年会上报道了这些研究结果。

Loss of growth control and intrinsic inhibitors of apoptosis may contribute to cancer survival by facilitating the mutations and by promoting resistance to various therapy. Meanwhile, the target molecule therapy against cancer has been widely accepted and various target molecular therapeutic agents are developed. Bcl-2 and Bcl-xL proteins are the member of Bcl-2 family, which have been shown to protect cells from some forms of apoptosis. In addition, overexpression of these molecules is believed to contribute to malignant cells expansion by means of anti-apoptotic effect. Tetrocarcin A(TC-A), on the other hand, a novel anti-tumor antibiotic was isolated from the culture broth of Micromonospora chalcea KY11091 through various procedures. Recently, TC-A was verified as an inhibitor of the anti-apoptotic molecule, Bcl-2 and/or Bcl-xL in T cell lines, and promoted apoptosis through the mitochondrial pathway. Here, we examined the effects of TC-A on Bcl-2 and/or Bcl-xL overexpressed human breast cancer cells such as MDA-231, ZR75-1, and KPL-1. Low concentration (2.5 μM) of TC-A induced typical apoptosis in all these cells via mitochondrial pathway. Western blotting analyses, however, have shown none of effects on these molecules expression. In conclusion, TC-A, anti-biotics, appears to be a novel agent that induces apoptosis on Bcl-2 and/or Bcl-xL overexpressed human breast cancers, while its precise mechanism is unknown. Based on these results, TC-A would become a novel chemotherapeutic agent for chemotherapy resistant human breast cancers.We reported those results of research in the 2003 and 2004 Annual Congress of Japan Surgical Society, and the 2004 Annual Congress of Japanese Breast Cancer Society.