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J Cancer 2022; 13(7):2362-2373. doi:10.7150/jca.71263 This issue Cite

Review

Low Intensity Ultrasound as an Antidote to Taxane/Paclitaxel-induced Cytotoxicity

Celina Amaya¹, Elizabeth R. Smith², Xiang-Xi Xu^1,3✉

1. Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136
2. Department of Obstetrics, Gynecology and Reproductive Science, University of Miami Miller School of Medicine, Miami, FL 33136
3. Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, 1120 NW 14th Street, Miami, FL, USA

✉ Corresponding author: xxu2miami.edu

Abstract

The taxane family of compounds, including Taxol/paclitaxel and Taxotere/docetaxel, are surprisingly successful drugs used in combination or alone for the treatment of most major solid tumors, especially metastatic cancer. The drugs are commonly used in regimen with other agents (often platinum drugs) as frontline treatment, or used as a single agent in a dose dense regimen for recurrent cancer. The major side effects of taxanes are peripheral neuropathy, alopecia, and neutropenia, which are grave burden for patients and limit the full potential of the taxane drugs. Especially in the current treatment protocol for peripheral neuropathy, taxane dosage is reduced once the symptoms present, resulting in the loss of full or optimal cancer killing activity.

Substantial efforts have been made to address the problem of cytotoxic side effects of taxanes, though strategies remain very limited. Following administration of the taxane compound by infusion, taxane binds to cellular microtubules and is sequestered within the cells for several days. Taxane stabilizes and interferes with microtubule function, leading to ultimate death of cancer cells, but also damages hair follicles, peripheral neurons, and hemopoietic stem cells. Currently, cryo-treatment is practiced to limit exposure and side effects of the drug during infusion, though the effectiveness is uncertain or limited.

A recent laboratory finding may provide a new strategy to counter taxane cytotoxicity, that a brief exposure to low density ultrasound waves was sufficient to eliminate paclitaxel cytotoxicity cells in culture by transiently breaking microtubule filaments, which were then relocated to lysosomes for disposal. Thus, ultrasonic force to break rigid microtubules is an effective solution to counter taxane cytotoxicity. The discovery and concept of low intensity ultrasound as an antidote may have the potential to provide a practical strategy to counter paclitaxel-induced peripheral neuropathy and alopecia that resulted from chemotherapy.

Taxanes are a class of important drugs used in chemotherapy to treat several major cancers. This article reviews a new laboratory discovery that ultrasound can be used as an antidote for the peripheral cytotoxicity of taxane drugs and discusses the potential development and application of low intensity ultrasound to prevent side effects in chemotherapeutic treatment of cancer patients.

Keywords: Ultrasound, shock wave, microtubules, Taxol/paclitaxel, cytotoxicity, peripheral neuropathy, alopecia, neutropenia, cancer chemotherapy, side effects

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