Taxanes and platinum derivatives impair Schwann cells via distinct mechanisms

Abstract

Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy-induced peripheral neuropathy (CIPN), however, the precise underlying mechanisms are not fully understood. Here, we examined the direct effects of anti-cancer agents on Schwann cells. Exposure of primary cultured rat Schwann cells to paclitaxel (0.01 μM), cisplatin (1 μM), or oxaliplatin (3 μM) for 48 h induced cytotoxicity and reduced myelin basic protein expression at concentrations lower than those required to induce neurotoxicity in cultured rat dorsal root ganglion (DRG) neurons. Similarly, these anti-cancer drugs disrupted myelin formation in Schwann cell/DRG neuron co-cultures without affecting nerve axons. Cisplatin and oxaliplatin, but not paclitaxel, caused mitochondrial dysfunction in cultured Schwann cells. By contrast, paclitaxel led to dedifferentiation of Schwann cells into an immature state, characterized by increased expression of p75 and galectin-3. Consistent with in vitro findings, repeated injection of paclitaxel increased expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerve. These results suggest that taxanes and platinum derivatives impair Schwan cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, which may be important in the development of CIPN in conjunction with their direct impairment in peripheral neurons.

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…Platinum derivatives induced mitochondrial dysfunction in cultured Schwann cells, while paclitaxel led to the dedifferentiation of Schwann cells into an immature state characterized by increased expression of p75 and galectin-3. In line with this, in the mouse sciatic nerve, repeated injection of paclitaxel increased the expression of p75 and galectin-3 in Schwann cells [145].…”

SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair

“…Interestingly, we observed cisplatin-induced nuclear accumulation of SIRT2 that resulted in an approximately 4-fold increase in nuclear SIRT2 in 50B11 neurons, as assessed via IF ( Figure 2, A and B). A 5.5-fold increase was observed when assessed via frac- clonal antibody specific for cisplatin-GG adducts, a major mechanism of cisplatin-induced DNA damage (8)(9)(10). Compared with parental DRG neurons, increased amounts of DNA adduct were detected in Sirt2-KO cells ( Figure 3, C and D).…”

“…Antineoplastic treatments have been shown to be cytotoxic to Schwann cells through the formation of inclusion bodies and vacuoles, whereas proliferation of Langerhans cells in the skin is a by-product of inflammation and leads to the loss of intraepidermal nerve fibers. Similarly, inflammatory mechanisms can induce the accumulation of macrophages in dorsal root ganglia (DRG), leading to injury and peripheral neuropathy (7)(8)(9).…”

Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by delaying axon degeneration

“…Many chemotherapeutic agents invariably cause peripheral neurotoxicity, leading to permanent neuronal dysfunction [75][76][77][78][79] . Under conditions of denervation, Schwann cells become strongly susceptible to chemotoxicity 80 . We wondered if the protracted maintenance of severed axons in Sarm1 mutants may suppress glial vulnerability.…”