Taxanes in chemotherapy: why healthy cells are affected too

Taxanes — paclitaxel, docetaxel, and cabazitaxel — are among the core first-line chemotherapy drugs used to treat many types of cancer, including ovarian and breast cancer. Their clinical effectiveness is so substantial that avoiding these treatment regimens may significantly reduce a patient’s chances of recovery.

However, such powerful therapy also has a serious downside. The mechanism behind tumor-cell death involves forcibly stopping cell division: taxanes bind to beta-tubulin within microtubules, disrupt their dynamics, and abnormally stabilize the filaments. As a result, mitosis is blocked, the nuclear envelope breaks down, and cell death is triggered. The problem is that this process is not selective. The drugs also disrupt the life cycle of healthy, rapidly dividing cells, so treatment is inevitably associated with serious adverse effects, including peripheral neuropathy, suppression of blood-cell production (myelosuppression), and hair loss (alopecia) [1].

Alopecia as an adverse effect: a physical and psychological burden

Scalp hair follicles are particularly vulnerable because matrix cells in the active growth phase, or anagen, divide continuously to form the hair shaft. Under normal conditions, 85–90% of scalp follicles are in this phase at any given time. As a result, taxanes can cause toxic effects quickly: hair shedding may begin as early as 1–3 weeks after the first treatment cycle. More than 80% of patients receiving paclitaxel develop scalp alopecia; the eyebrows, eyelashes, and beard may also be affected. Hair regrowth usually takes 3–6 months after the chemotherapy regimen is completed, although hair loss can be persistent or irreversible in some cases.

For patients with cancer, hair loss is far more than a cosmetic inconvenience. It is a difficult experience that can profoundly alter a person’s familiar body image, lower self-esteem, and serve as a constant visible reminder of the disease. Hair loss adds another negative element to an already challenging emotional state. This unfavorable psychological background, together with chronic stress, may in turn weaken the body’s resources in coping with illness.

Scalp cooling remains the only clinically established method currently used to help prevent chemotherapy-induced alopecia. Lowering the temperature causes vasoconstriction and reduces the delivery of the cytotoxic drug to the hair follicles. The procedure is performed during intravenous administration of the chemotherapy drug, but its effectiveness varies. It can also cause considerable discomfort, including chills, persistent headache, and neck pain, while leaving the eyebrows and eyelashes completely unprotected [2].

Cyclin-dependent kinase inhibitors: an attempt to switch off follicle-cell division

Scalp cooling is a strictly local intervention, whereas the clinical challenge is broader: protecting hair throughout the body, including the eyebrows and eyelashes. Researchers therefore turned to systemic pharmacological strategies, including temporarily pausing division in hair-matrix cells while the cytotoxic drug circulates. One such approach involves inhibitors of cyclin-dependent kinases (CDKs).

The idea is to temporarily arrest the cell cycle in hair-matrix cells, making them less vulnerable to the antimitotic effects of taxanes—in much as tumor cell division is halted.

Early experiments with a CDK2 inhibitor in rodent models appeared promising. However, researchers later retracted the findings because they could not reproduce the results. Subsequent research shifted toward CDK4/6 inhibitors — palbociclib, ribociclib, and abemaciclib — which are already used in the treatment of breast cancer. Temporary CDK4/6 inhibition was shown to protect hematopoietic stem cells in the bone marrow from chemotherapy-induced exhaustion. In organ cultures of human hair follicles, these drugs also prevented paclitaxel-induced follicular damage [3]. However, CDK4/6 inhibitors themselves have been associated with alopecia when used to treat breast cancer, which considerably reduces enthusiasm for developing them specifically as a preventive treatment for hair loss.

Low-intensity ultrasound: mechanism of action and a potential treatment schedule

Because systemic use of cell-cycle inhibitors is associated with significant adverse effects, researchers began exploring a fundamentally different, physical approach to follicle protection: low-intensity ultrasound (LIUS).

The discovery was largely serendipitous. In cell cultures, brief exposure to low-intensity ultrasound—approximately 1 W/cm² for 2–5 minutes—had little effect on cell proliferation but eliminated paclitaxel's cytotoxicity [4]. Ultrasound at this intensity temporarily disrupts the microtubule cytoskeleton.

The proposed protective mechanism is as follows: taxanes stabilize microtubules and make them abnormally rigid. Ultrasound physically disrupts these drug-bound, rigid filaments, after which their fragments are transported to lysosomes for degradation. Because tubulin production within the cell is autoregulated, drug-free tubulin rapidly forms a new, functional microtubule network. The cell can therefore avoid mitotic arrest and subsequent cell death.

The effect was confirmed in organ cultures of human hair follicles. Brief exposure to low-intensity ultrasound significantly reduced paclitaxel-induced mitotic arrest and apoptosis in follicular cells, effectively protecting the hair bulbs from drug-related damage [5]. The method's ability to prevent paclitaxel-induced follicular damage was also demonstrated in live mice.

Importantly, the proposed local application of ultrasound to the scalp is expected to disrupt drug-bound microtubules specifically in follicular cells without interfering with microtubule stabilization or the cytotoxic activity of taxanes in tumor cells elsewhere in the body.

Based on the pharmacokinetics of paclitaxel, the chemotherapy drug is administered intravenously over 3–6 hours. Its plasma concentration falls rapidly after the infusion ends, while its cellular toxicity in tissues persists for several days. The authors therefore propose a potential treatment schedule consisting of ultrasound sessions lasting approximately 5 minutes at an intensity of about 1 W/cm², performed within approximately 4–10 hours after completion of the chemotherapy infusion.

The rationale is to minimize the period during which residual drug can affect the follicles, when its plasma concentration has already fallen substantially. The authors also note that the scalp acts as a natural barrier to low-frequency ultrasound, making it unlikely that the energy used in this approach would reach the brain structures.

Limitations and potential clinical value

The available data were obtained primarily from cell cultures, hair-follicle organ cultures, and mouse models. In addition, research on low-intensity ultrasound has focused mainly on protecting scalp hair follicles. Although taxanes may also damage the follicles of the eyebrows, eyelashes, beard, and other parts of the body, the article did not investigate using ultrasound to prevent alopecia in these areas. The available results therefore cannot yet be extrapolated to all areas of body hair.

Before introducing the method into clinical practice, further studies are needed to determine the optimal device type, intensity, treatment duration, and timing, and to confirm the approach's effectiveness and safety in patients. Treating different anatomical areas, particularly the face and the skin around the eyes, will require separate evaluation.

Nevertheless, low-intensity ultrasound is of interest as a potentially localized and more comfortable way to protect hair follicles. In the future, it may complement or expand the options currently available for preventing taxane-induced alopecia.

Conclusion

The search for ways to preserve hair during taxane-based chemotherapy remains an active area of research. Alongside scalp cooling, which is already used in clinical practice, and experimental CDK4/6 inhibitors, low-intensity ultrasound offers a fundamentally new, mechanism-based approach. In the future, it may help reduce the psychological burden of alopecia for millions of patients undergoing taxane treatment for cancer.

References

1. Amaya C., Schlumbrecht M.P., Wikramanayake T.C., Xu X.X. Mechanism-based strategies for prevention of taxane-induced hair follicle damage in cancer chemotherapy. Cancers 2026; 18(9): 1351.
2. Purba T.S., Ng'andu K., Brunken L. et al. CDK4/6 inhibition mitigates stem cell damage in a model for taxane-induced alopecia. EMBO Mol Med 2019; 11: e11031.
3. Wikramanayake T.C., Haberland N.I., Akhundlu A., Laboy Nieves A., Miteva M. Prevention and treatment of chemotherapy-induced alopecia: what is available and what is coming? Curr Oncol 2023; 30(4): 3609–3626.
4. Amaya C., Luo S., Baigorri J. et al. Exposure to low-intensity ultrasound removes paclitaxel cytotoxicity in breast and ovarian cancer cells. BMC Cancer 2021; 21: 981.
5. Cheret J., Samra T., Verling S.D. et al. Low-intensity ultrasound as a potential intervention strategy to protect human scalp hair follicles from taxane-induced toxicity. J Investig Dermatol 2023; 143(9): 1809–1813.e2.