Paclitaxel (Taxol) is a microtubule-stabilizing drug used to treat several solid tumors, including ovarian, breast, non-small cell lung, and pancreatic cancers. The current treatment of ovarian cancer is chemotherapy using paclitaxel in combination with carboplatin as a frontline agent, and paclitaxel is also used in salvage treatment as a second line drug with a dose intensive regimen following recurrence. More recently, a dose dense approach for paclitaxel has been used to treat metastatic breast cancer with success. Paclitaxel binds to beta tubulin with high affinity and stabilizes microtubule bundles. As a consequence of targeting microtubules, paclitaxel kills cancer cells through inhibition of mitosis, causing mitotic catastrophes, and by additional, not yet well defined non-mitotic mechanism(s). In exploring methods to modulate activity of paclitaxel in causing cancer cell death, we unexpectedly found that a brief exposure of paclitaxel-treated cells in culture to low intensity ultrasound waves prevented the paclitaxel-induced cytotoxicity and death of the cancer cells. The treatment with ultrasound shock waves was found to transiently disrupt the microtubule cytoskeleton and to eliminate paclitaxel-induced rigid microtubule bundles. When cellular microtubules were labelled with a fluorescent paclitaxel analog, exposure to ultrasound waves led to the disassembly of the labeled microtubules and localization of the signals to perinuclear compartments, which were determined to be lysosomes. We suggest that ultrasound disrupts the paclitaxel-induced rigid microtubule cytoskeleton, generating paclitaxel bound fragments that undergo degradation. A new microtubule network forms from tubulins that are not bound by paclitaxel. Hence, ultrasound shock waves are able to abolish paclitaxel impact on microtubules. Thus, our results demonstrate that a brief exposure to low intensity ultrasound can reduce and/or eliminate cytotoxicity associated with paclitaxel treatment of cancer cells in cultures.

中文翻译：

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暴露于低强度超声可消除紫杉醇对乳腺癌和卵巢癌细胞的细胞毒性


紫杉醇（Taxol）是一种微管稳定药物，用于治疗多种实体瘤，包括卵巢癌、乳腺癌、非小细胞肺癌和胰腺癌。目前卵巢癌的治疗方法是使用紫杉醇联合卡铂作为一线药物进行化疗，紫杉醇也作为二线药物用于复发后的剂量密集方案的挽救治疗。最近，紫杉醇的剂量密集方法已成功用于治疗转移性乳腺癌。紫杉醇以高亲和力与 β 微管蛋白结合并稳定微管束。由于靶向微管，紫杉醇通过抑制有丝分裂、导致有丝分裂灾难以及通过其他尚未明确定义的非有丝分裂机制来杀死癌细胞。在探索调节紫杉醇引起癌细胞死亡的活性的方法时，我们意外地发现将培养中的紫杉醇处理的细胞短暂暴露于低强度超声波可以防止紫杉醇诱导的细胞毒性和癌细胞死亡。发现超声冲击波治疗会暂时破坏微管细胞骨架并消除紫杉醇诱导的刚性微管束。当细胞微管用荧光紫杉醇类似物标记时，暴露于超声波导致标记的微管解体并将信号定位到核周区室，该区室被确定为溶酶体。我们建议超声破坏紫杉醇诱导的刚性微管细胞骨架，产生发生降解的紫杉醇结合片段。新的微管网络由不受紫杉醇结合的微管蛋白形成。 因此，超声冲击波能够消除紫杉醇对微管的影响。因此，我们的结果表明，短暂暴露于低强度超声可以减少和/或消除与紫杉醇治疗培养物中的癌细胞相关的细胞毒性。