Cbl-b调控蟾毒灵与化疗药物协同诱导乳腺癌细胞凋亡的机制研究

Breast cancer is the most common cause of death from cancer in women. The majority of metastatic breast cancer have developed resistance to the drugs that has been used. Therefore,new treatment strategies are needed for this disease. Bufalin, a major active ingredient of the traditional Chinese medicine ChanSu, induces cell apoptosis in multiple types of cancer cells. But the toxicity of bufalin limit its clinical application. Our recent study showed that bufalin could enhance TRAIL-induced apoptosis in breast cancer cells. Our preliminary study found that bufalin and some chemotherapeutics could synergistically surpress breast cancer cells proliferation. In the present study, we aim to search the chemotherapeutics that could synergistically induce breast cancer cells apoptosis with bufalin, and explore the possible mechanism. The fate of cells is known to depend on the balance between survival and death signals within cells. It is reported that bufalin could activate the death signals,and suppress the survival signals. Cbl-b could regulate the activation of cell signals and the aggregation of raft. The aim of the present study was to investigate the effect of the death, survival signals and Cbl-b in the synergistic effect of bufalin and chemotherapeutics.

乳腺癌是女性最常见的恶性肿瘤之一，大部分发生远处转移的患者对前期用药产生耐药，因此急需探索新的药物以提高乳腺癌的治疗疗效。蟾毒灵（Bufalin）是中药蟾酥的主要活性成分，可抑制肿瘤细胞的增殖，诱导细胞凋亡，但浓度相关性毒性限制了其在临床上的应用。降低Bufalin的给药浓度是将其推向临床的有效途径，我们的研究发现相对低浓度的Bufalin可增强TRAIL诱导的乳腺癌细胞凋亡，本课题将扩大研究范围，筛选可与Bufalin协同诱导乳腺癌细胞凋亡的化疗药物，并探索协同作用的可能机制。细胞的命运决定于细胞内存活信号与死亡信号的"动态平衡"，泛素连接酶Cbl-b是调节死亡信号与存活信号活化的重要因子，同时可调节信号活化的平台"脂筏"的聚集，本课题将研究Cbl-b在Bufalin与化疗药物协同作用中扮演的角色，为Bufalin真正走向临床提供科学依据。

乳腺癌是导致女性死亡的最常见恶性肿瘤，化疗是其主要治疗手段之一，化疗耐药严重限制了临床的治疗疗效。蟾毒灵是抗肿瘤中药蟾酥的主要活性成分，可诱导多种肿瘤细胞凋亡。本课题中我们探索了蟾毒灵对乳腺癌细胞增殖的抑制，以及其与化疗药物联合作用于乳腺癌细胞是否可增强乳腺癌细胞对化疗药物的敏感性，并探索了可能的机制。结果发现，蟾毒灵可以通过下调细胞存活信号通路活性、上调死亡信号通路的活性抑制不同乳腺癌细胞系的增殖，诱导细胞凋亡。进一步研究发现低浓度的蟾毒灵可以与紫杉醇、顺铂、阿霉素、氟尿嘧啶等协同抑制乳腺癌细胞增殖，协同的机制包括：调节Cbl-b的表达，促进脂筏的聚集，下调c-Met、c-Src，AKT等细胞存活信号的活性，上调p38、caspase-8等死亡信号活性，下调XIAP、c-Flip等凋亡抑制蛋白的表达等。本课题研究结果为含蟾毒灵的中成药与化疗药物联合应用于乳腺癌的治疗奠定了理论基础，为逆转乳腺癌的化疗耐药提供了潜在的靶点，有助于提高乳腺癌的化疗疗效。