The molecular and cellular insight into the toxicology of bortezomib-induced peripheral neuropathy

Yan, Wenping; Wu, Zhenxing; Zhang, Yuyu; Hong, Dongsheng; Dong, Xihao; Liu, Lin; Rao, Yuefeng; Huang, Lili; Zhang, Xiangnan; Wu, Jiaying

doi:10.1016/j.biopha.2021.112068

Cited by 19 publications

(23 citation statements)

References 84 publications

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“…Future experiments should test more classes of neuropathy-inducing cytostatics, such as platinum compounds or vinca alkaloids. Moreover, co-culture approaches, e.g., by introducing Schwann cells, may allow for the investigation of further neuropathy-relevant aspects since glia may take important roles in neuropathic diseases [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro

Holzer

Suciu

Karreman

et al. 2022

IJMS

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Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors. A two-step differentiation protocol, involving the transient expression of ectopic neurogenin-1 (NGN1) allowed for the generation of homogeneous cultures of sensory neurons. After >38 days of differentiation, they showed a robust response (Ca2+-signaling) to the P2X3 ligand α,β-methylene ATP. The clinical proteasome inhibitor bortezomib abolished the P2X3 signal at ≥5 nM, while 50–200 nM was required in the PeriTox test to identify neurite damage and cell death. A 24 h treatment with low nM concentrations of bortezomib led to moderate increases in resting cell intracellular Ca2+ concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca2+ influx remained unaffected. We interpreted the specific attenuation of purinergic signaling as a functional cell stress response. A reorganization of tubulin to form dense structures around the cell somata confirmed a mild, non-cytotoxic stress triggered by low concentrations of bortezomib. The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons.

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Section: Discussionmentioning

confidence: 99%

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro

Holzer

Suciu

Karreman

et al. 2022

IJMS

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“…More than 30% of patients receiving bortezomib alone or in combination with other drugs have been reported to develop peripheral neuropathy (bortezomib-induced peripheral neuropathy, BIPN) (27), characterized by neuropathic pain. The pathological mechanism of BIPN may include: (i) demyelination, formation of aggregates, endoplasmic reticulum stress, inhibition of dedifferentiation of Schwann cells, (ii) neuronal dysfunction [hyperactivity of wide dynamic range (WDR) neurons in the spinal dorsal horn, damage of afferent sensory neuron cell bodies located in the dorsal root ganglia (DRG) of the spinal cord, abnormality of ion channel, imbalance of tubulin dynamics, mitochondrial dysfunction, inflammation in DRG neurons], (iii) astrocyte activation, and (iv) macrophage infiltration (10). When human induced pluripotent stem cell-derived sensory neurons were exposed to a clinically relevant dose of bortezomib, alterations in microtubule-associated proteins (especially significant reduction of MAP2c) occurred, suggesting a multifaceted relationship between bortezomib-induced proteotoxicity and microtubule cytoskeletal architecture (28).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies reported adverse effects of anticancer drugs such as cardiotoxicity (3,4), neurotoxicity (5,6), and keratinocyte toxicity (7,8). Bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma, has been reported to induce potent neurotoxicity (9,10). Since polyphenols such as curcumin (11), resveratrol (12), chlorogenic acid (13, 14), and p-coumaric acid (15) (Figure 1) daily taken from curry, wine, coffee, and various food materials have been reported to show neuroprotective activity, the present study was undertaken to investigate whether these compounds can protect differentiating P12 neuronal cells from the bortezomibinduced insult (9) (Figure 2) without affecting the anticancer activity.…”

mentioning

confidence: 99%

Inhibition of Neurotoxicity/Anticancer Activity of Bortezomib by Caffeic Acid and Chlorogenic Acid

Matsuda¹,

Sakagami²,

Amano³

et al. 2022

Anticancer Res

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Background/Aim: Bortezomib, used for the treatment of multiple myeloma, has been reported to induce potent neurotoxicity. The present study investigated whether eight popular polyphenols inhibit bortezomib-induced neurotoxicity without affecting its anticancer activity. Materials and Methods: Viable cell number was determined with the MTT method. Tumor-specificity was determined by the relative cytotoxicity in human oral squamous cell carcinoma vs. normal oral cells. Neurotoxicity was determined by the relative cytotoxicity in differentiated rat neuronal PC12 cells vs. normal cells. Apoptotic cells were quantified by cell cycle analysis. Results: Bortezomib induced cell shrinkage, disruption of neurites, and accumulation of PC-12 cells in subG1. Only chlorogenic acid and caffeic acid protected PC-12 cells from bortezomib-induced neurotoxicity.Ferulic acid that has one of the two hydroxyl groups replaced by a methoxy group showed a significantly reduced neuroprotective effect. Caffeic acid and the chlorogenic acid also neutralized the anticancer potential of bortezomib. Conclusion: Caffeic acid and the chlorogenic acid may reduce the biological activity of bortezomib by forming a conjugate.

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“…26 For these reasons, second-generation inhibitors were developed, as carfilzomib and ixazomib; however, carfilzomib has a significant myocardial toxicity as well, while neuropathy is still observed with ixazomib. 27 Proteasome inhibitors can directly elicit apoptosis of cancer cells by altering cell cycle control and by promoting the accumulation of unfolded and misfolded proteins. Interestingly, bortezomib was also shown to be effective in PCa cells, with a p21-dependent mechanism, and in human prostate tumor xenografts 20,28 ; consequently, its use in patients with PCa is under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Bortezomib, a dipeptide boronic acid derivative, was the first approved proteasome inhibitor and showed a potent antitumor activity; however, its use is limited by a significant toxicity, especially peripheral neuropathy, and by the development of resistance 26 . For these reasons, second‐generation inhibitors were developed, as carfilzomib and ixazomib; however, carfilzomib has a significant myocardial toxicity as well, while neuropathy is still observed with ixazomib 27 . Proteasome inhibitors can directly elicit apoptosis of cancer cells by altering cell cycle control and by promoting the accumulation of unfolded and misfolded proteins.…”

Section: Discussionmentioning

confidence: 99%

HDL‐mediated reduction of cholesterol content inhibits the proliferation of prostate cancer cells induced by LDL: Role of ABCA1 and proteasome inhibition

et al. 2022

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High‐density lipoproteins (HDL) are well known for their atheroprotective function, mainly due to their ability to remove cell cholesterol and to exert antioxidant and anti‐inflammatory activities. Through the same mechanisms HDL could also affect the development and progression of tumors. Cancer cells need cholesterol to proliferate, especially in hormone‐dependent tumors, as prostate cancer (PCa). Aim of the study was to investigate the ability of HDL to modulate cholesterol content and metabolism in androgen receptor (AR)‐positive and AR‐null PCa cell lines and the consequences on cell proliferation. HDL inhibited colony formation of LNCaP and PC3 cells. HDL reduced cell cholesterol content and proliferation of LNCaP cells loaded with low‐density lipoproteins but were not effective on PC3 cells. Here, the expression of the ATP‐binding cassette transporter A1 (ABCA1) was markedly reduced due to proteasome degradation. Bortezomib, a proteasome inhibitor, restored ABCA1 expression and HDL ability to promote cholesterol removal from PC3; consequently, HDL inhibited the proliferation of PC3 cells induced by LDL only after bortezomib pre‐treatment. In conclusion, the antiproliferative activity of HDL on AR‐positive and AR‐null PCa cells also rely on cholesterol removal, a process in which the ABCA1 transporter plays a key role.

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The molecular and cellular insight into the toxicology of bortezomib-induced peripheral neuropathy

Cited by 19 publications

References 84 publications

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro

Inhibition of Neurotoxicity/Anticancer Activity of Bortezomib by Caffeic Acid and Chlorogenic Acid

HDL‐mediated reduction of cholesterol content inhibits the proliferation of prostate cancer cells induced by LDL: Role of ABCA1 and proteasome inhibition

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