Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Sep;1(9):639-49.
doi: 10.1002/acn3.90. Epub 2014 Sep 2.

Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients

Gigi J Ebenezer  1 , Karen Carlson  2 , Diana Donovan  2 , Marta Cobham  2 , Ellen Chuang  2 , Anne Moore  2 , Tessa Cigler  2 , Maureen Ward  2 , Maureen E Lane  2 , Anita Ramnarain  2 , Linda T Vahdat  2 , Michael Polydefkis  1
Affiliations

Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients

Gigi J Ebenezer et al. Ann Clin Transl Neurol. 2014 Sep.

Abstract

Background: We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule-stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism.

Methods: Ten breast cancer patients receiving Ix underwent total neuropathy score clinical (TNSc) assessment, distal leg skin biopsies at cycle (Cy) 3 (80-90 mg/m(2)), Cy5 (160-190 mg/m(2)), and Cy7 (>200 mg/m(2)) and were compared to 5 controls. Skin blocks were processed for EM and ultrastructural morphometry of Remak axons done.

Results: At baseline, Ix-treated subjects had higher TNSc values (4.5 ± 0.8 vs. 0.0 ± 0.0), greater percentage of empty (denervated) Schwann cells (29% vs. 12%), altered axonal diameter (422.9 ± 17 vs. 354.9 ± 14.8 nm, P = 0.01), and axon profiles without mitochondria tended to increase compared to control subjects (71% vs. 70%). With increasing cumulative Ix exposure, an increase in TNSc values (Cy3: 5.4 ± 1.2, Cy7: 10 ± 4, P < 0.001), empty Schwann cells (39% by Cy7), and dilated axons (in nm, Cy3: 506.3 ± 22.1, Cy5: 534.8 ± 33, Cy7: 527.8 ± 24.4; P < 0.001) was observed. In addition, axon profiles without mitochondria (Cy3:74%, Cy7:78%) and mitochondria with abnormal morphology (grade 3 or 4) increased from 24% to 79%. Schwann cells with atypical mitochondria and perineuronal macrophage infiltration in dermis were noted.

Interpretation: This study provides functional and structural evidence that Ix exposure induces a dose-dependent toxicity on small sensory fibers with an increase in TNSc scores and progressive axonal loss. Mitochondria appear to bear the cumulative toxic effect and chemotherapy-induced toxicity can be monitored through serial skin biopsy-based analysis.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Subepidermal Remak Schwann cell and a small cutaneous nerve in distal leg. (A) Two Remak Schwann cells with unmyelinated axons (arrows) remaining in the papillary dermis. These have also been referred to as: subepidermal nerve bundles. (B) A small cutaneous nerve in the deeper dermis containing many Remak Schwann cells with unmyelinated axons arranged in bundles (arrows) enclosed by perineurium (slashed arrow) and partly by epineurium (arrow head). Scale bars A and B = 2 μm.
Figure 2
Figure 2
Peripheral neuropathy in ixabepilone-treated subjects. The total neuropathy score clinical progressively increased (P ≤ 0.0001) with the total cumulative dose of Ixabepilone.
Figure 3
Figure 3
Remak Schwann cells in ixabepilone (Ix)-treated patients. (A) Electron micrograph of Remak Schwann cells containing normal axons with predominantly circular profiles (arrows, Ax-boxed) and few oblique profiles of microtubules. A slashed arrow identifies a denervated Remak Schwann cell. Scale bar = 1 μm. (B) The number of axons per Remak Schwann cells across the treatment group significantly decreased with increasing cumulative Ix dose, and was consistent with severe progressive axonal loss. In Ix-treated subjects, there was an increase in denervated Remak Schwann cells from 29% at baseline to 39% by cycle 7. The chi-square distribution for the different chemotherapy groups and the control group is highly significant (P < 0.001). (C) The number of axons per Schwann cell was linear and decreased with increasing cycle number (P = 0.02).
Figure 4
Figure 4
Electron micrographs of axonal changes in Ixabepilone-treated patients. (A) A distended axon (Ax) with part of the axoplasm (slashed arrow) undergoing degeneration. A large Remak Schwann cell containing degenerating axons in varying sizes (arrows), an axon exhibiting watery axoplasm with microvesicles (slashed arrow), and an atypical mitochondrion (arrow head). Portions of degenerating axonal membranes (warped arrows) are exposed to dermal collagen. (B) The axonal diameter in Ix-treated patients are larger and significantly increased from baseline. (C) A large Remak Schwann cell (Sch) with absence of axons but with preserved mesaxons (arrows). (D) A Remak Schwann cell with an axon (1) showing partitioned axoplasm with central sequestration (2) of degrading cytoskeletal structures (slashed arrow) and impinged by dilated lysosomal vesicles (arrows). The adjacent obliquely transected axon showing a long atypical mitochondria undergoing fragmentation (arrow head). Scale bars: A = 500 nm, C and D = 1 μm.
Figure 5
Figure 5
Effect of Ixabepilone on axonal mitochondria of Remak Schwann cells. (A) In patients with increasing chemotherapy cycles, axons trended toward progressive loss of mitochondria. (B) 82% of mitochondria from control subjects (baseline only) had normal (grade 0 or 1) morphology. Among Ix-treated subjects, there was a dose-dependent decrease in the percentage of mitochondria with normal (grade 0 or 1) morphology (P < 0.001). The thick black line represents the regression line for Ix-treated subjects. (C) After seven cycles of Ix (>200 mg/m2), 79% of mitochondria exhibited severe atypical morphology (grade 3 or 4) compared to 15.5% of mitochondria from control subjects. Increasing cumulative ixabepilone exposure was strongly associated with an increase in the percentage of mitochondria with dysmorphic morphology (P < 0.001). The thick black line represents the regression line for Ix-treated subjects.
Figure 6
Figure 6
Electron micrographs of axonal mitochondrial changes of Remak Schwann cells in Ixabepilone-treated patients. (A) Axons of Remak Schwann cell exhibiting atypical mitochondria with loss of cristae and homogenous matrix (arrows). An autophagosome (arrow head) is seen adjacent to a degenerating axon with atypical mitochondria. (B) A subepidermal (epidermis-slashed arrows) Remak Schwann cell with the axonal mitochondria showing vacuolization (arrow), and stacking of lamellated Schwann cell processes (arrow head). (C) A small cutaneous nerve bundle (* perineurium) with the axons exhibiting atypical mitochondria undergoing fragmentation (arrows). Scale bars: A = 1 μm, B and C = 500 nm.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55:10–30. - PubMed
    1. Howlader N, Noone AM, Yu M, et al. Use of imputed population-based cancer registry data as a method of accounting for missing information: application to estrogen receptor status for breast cancer. Am J Epidemiol. 2012;176:347–356. - PMC - PubMed
    1. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979;277:665–667. - PubMed
    1. Vahdat LT, Papadopoulos K, Balmaceda C, et al. Phase I trial of sequential high-dose chemotherapy with escalating dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer. Clin Cancer Res. 1998;4:1689–1695. - PubMed
    1. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25:3407–3414. - PubMed

LinkOut - more resources