PURPOSETo update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors.METHODSAn...

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.20.01399

Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update

Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN.

https://www.mdpi.com/1422-0067/22/2/888/pdf

Pathological mechanisms of bortezomib-induced peripheral neuropathy

Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase-interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders. SIGNIFICANCE STATEMENT: Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase-interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.

https://pharmrev.aspetjournals.org/content/pharmrev/73/1/59.full-text.pdf

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain

Chemotherapy-induced peripheral neuropathy (CIPN) is a common cause of pain and poor quality of life for those undergoing treatment for cancer and those surviving cancer. Many advances have been made in the pre-clinical science; despite this, these findings have not been translated into novel preventative measures and treatments for CIPN. This review aims to give an update on the pre-clinical science, preventative measures, assessment and treatment of CIPN.

/pdf/recent-advances-in-understanding-chemotherapy-induced-4wp7hiotwb.pdf

Recent advances in understanding chemotherapy-induced peripheral neuropathy.

Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming with AMPK activators in male and female mice.

Peripheral sensory neuropathy is the most prominently reported adverse effect of oxaliplatin. The purpose of this study was to evaluate metformin role in oxaliplatin-induced neuropathy. From November 2014 to May 2016, 40 patients with stage III colorectal cancer completed 12 cycles of FOLFOX-4 regimen. Twenty patients in the control arm received FOLFOX-4 regimen only, and 20 patients in the metformin arm, received the same regimen along with metformin 500 mg three times daily. The metformin efficacy was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0), a12-item neurotoxicity questionnaire (Ntx-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group and, the brief pain inventory short form “worst pain” item. In addition to neurotensin, malondialdehyde and interleukin-6 serum levels assessment. At the end of the 12th cycle, there were less patients with grade 2 and 3 neuropathy in metformin arm as compared to control arm. (60 versus 95%, P = 0.009) In addition, metformin arm showed significantly higher total scores of Ntx-12 questionnaire than control arm (24.0 versus 19.2, P < 0.001). Furthermore, the mean pain score in metformin arm was significantly lower than those of control arm, (6.7 versus 7.3, P = 0.005). Mean serum levels of malondialdehyde and neurotensin were significantly lower in metformin arm after the 6th and the 12th cycles. Metformin may be a promising drug in protecting colorectal cancer patients against oxaliplatin-induced chronic peripheral sensory neuropathy.

Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study

Abstract Background Diabetic kidney disease (DKD) is a serious complication that begins with albuminuria and often leads to a rapid progressive decline in renal function. Niclosamide is a potent inhibitor of the Wnt/β-catenin pathway, which controls the expression of multiple genes of the renin–angiotensin–aldosterone system (RAAS), which in turn is influences the progression of DKD. This study was conducted to evaluate the effect of niclosamide as adjuvant therapy on DKD. Methods Out of 127 patients screened for eligibility, 60 patients completed the study. After randomization, 30 patients in the niclosamide arm received ramipril plus niclosamide, and 30 patients in the control arm received ramipril only for 6 months. The primary outcomes were the changes in urinary albumin to creatinine ratio (UACR), serum creatinine, and estimated glomerular filtration rate (eGFR). The secondary outcomes were measurements of urinary matrix metalloproteinase-7 (MMP-7), 8-hydroxy-2ʹ-deoxyguanosine (8-OHdG), and podocalyxin (PCX). Comparisons between the two arms were done using student t-test. Correlation analysis was done using Pearson correlation. Results Niclosamide decreased UACR by 24% (95% CI − 30 to − 18.3%) while there was a rise in UACR in the control arm by 11% (95% CI 4 to 18.2%) after 6 months (P &lt; 0.001). Moreover, a significant reduction in MMP-7 and PCX was noticed in the niclosamide arm. Regression analysis revealed a strong association between MMP-7, which is a noninvasive biomarker predicting the activity of the Wnt/β-catenin signaling, and UACR. A 1 mg/dL decline in MMP-7 level was associated with a 25 mg/g lowering in UACR (B = 24.95, P &lt; 0.001). Conclusion The addition of niclosamide to patients with diabetic kidney disease receiving an angiotensin-converting enzyme inhibitor significantly reduces albumin excretion. Further larger-scale trials are needed to confirm our results. Trial registration: The study was prospectively registered on clinicaltrial.gov on March 23, 2020, with identification code NCT04317430. 

/pdf/niclosamide-from-an-anthelmintic-drug-to-a-promising-3kfvbeyy.pdf

Basma Mahrous El-Fatatry

Papers

Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study

Niclosamide from an anthelmintic drug to a promising adjuvant therapy for diabetic kidney disease: randomized clinical trial