The role of MOTS-c-mediated antioxidant defense in aerobic exercise alleviating diabetic myocardial injury.

Myocardial remodeling and dysfunction are commonly observed in type 2 diabetes mellitus (T2DM). Aerobic exercise can partly alleviate diabetes-induced myocardial dysfunction through its antioxidant actions. MOTS-c is a potential exercise mimic. This study aimed to investigate the effects of MOTS-c on improving diabetic heart function and its mechanism and to identify whether MOTS-c improved antioxidant defenses due to aerobic exercise. Herein, we established a rat model of T2DM induced by high-fat diet combined with a low-dose streptozotocin injection. Interventions were performed using intraperitoneal injections of MOTS-c (i.p. 0.5 mg/kg/day, 7 days/week) or aerobic exercise training (treadmill, 20 m/min, 60 min/day, 5 days/week) for 8 weeks. Myocardial ultrastructure was assessed using transmission electron microscopy (TEM), myocardial lipid peroxidation levels (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) levels were assessed using colorimetric methods, and molecular analyses including MOTS-c, Kelch-like ECH-associated protein 1 (Keap1), Nuclear factor E2-related factor 2 (Nrf2), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)and phospho-AMPK (p-AMPK) were examined using Western blot. The results showed that MOTS-c, with or without exercise, reduced myocardial ultrastructural damage and improved glucolipid metabolism and cardiac function in T2DM. Furthermore, MOTS-c increased antioxidant markers such as SOD, CAT, and the protein expression of myocardial MOTS-c, Keap1, Nrf2, and p-AMPK. MOTS-c with exercise treatment reduced myocardial MDA and increased p-AMPK significantly comparing to only exercise or MOTS-c alone. Our findings suggest that MOTS-c may be a helpful supplement for overcoming exercise insufficiency and improving myocardial structure and function in diabetes.

Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

Pathogenic tau decreases nuclear tension in cultured neurons.

Neurodegenerative tauopathies, including Alzheimer's disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic destabilization of the lamin nucleoskeleton and formation of nuclear invaginations and blebs. Based on the known function of the nucleus as a mechanosensor, as well as the high incidence of nuclear pleomorphism in human Alzheimer's disease and related tauopathies, we investigated the effects of pathogenic tau on nuclear tension. We first find that tau-dependent nuclear envelope invagination and relocalization of LInker of Nucleoskeleton and Cytoskeleton (LINC) complex components are conserved in a newly-developed neuroblastoma cell line that features doxycycline-inducible expression of a tau mutant associated with autosomal dominant frontotemporal dementia. We next determine that a Förster resonance energy transfer (FRET)-based sensor of nuclear tension responds to cytoskeletal stabilization and destabilization when expressed in neuroblastoma cells. Using this nuclear tension sensor, we find that induced expression of pathogenic tau is sufficient to decrease nuclear tension. This work provides the initial proof-of-concept evidence that pathogenic forms of tau alter nuclear tension, paving the way for the future study of altered nuclear mechanosensing in the context of tau-mediated neurodegenerative disorders.

MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPß modification in rats.

AIMS: To determine the effects of the mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) and aerobic exercise on cardiac structure and function and explore the role of neuregulin-1 (NRG1)- ErbB2 receptor tyrosine kinase 4(ErbB4)- CCAAT-enhancer binding protein ß (C/EBPß) in cardiac physiological adaptation induced by MOTS-c and aerobic training. MAIN METHODS: We used Hematoxylin-Eosin staining(HE)and Transmission Electron Microscope (TEM) to observe the cardiac myocardial structure, carotid artery catheterization to test cardiac function, and real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting to describe the changes of NRG1, ErbB4, C/EBPß, and Gata in cardiac physiological adaptation. KEY FINDINGS: MOTS-c and aerobic training significantly increased heart weight and heart weight index (HWI) (all p < 0.05). Aerobic exercise and MOTS-c treatment thickened myocardial fibers, with a tendency of hypertrophy. Heart rate (HR) (p < 0.001, p = 0.010, p = 0.011), the isovolumic diastolic time constant (Tau) (p < 0.001, p < 0.001, p < 0.001) in exercised (E), MOST-c treated (M) and their combination (ME) decreased significantly, while the dP/dtmax (p < 0.001, p < 0.001, p = 0.039) and dP/dtmin (p < 0.001, p < 0.001, p = 0.001) in groups E, M and ME were significantly higher than those in group C, but EDP (p = 0.903, p = 0.708, p = 0.744) remained unchanged. Moreover, C/EBPß gene levels were significantly decreased in the differential gene expression between groups C and M transcriptomics sequencing. The levels of ErbB4 mRNA (p < 0.001, p < 0.001, p < 0.001) and Gata4 mRNA (p < 0.001, p < 0.001, p = 0.001) in groups E, M and ME increased significantly, while C/EBPß mRNA expression decreased significantly (p < 0.001, p = 0.002, p = 0.001), which was consistent with the results of transcriptome sequencing. NRG1 mRNA in group E was significantly higher than that in group C (p = 0.003), but there was no significant difference between groups M and ME (p = 0.804, p = 0.320). The protein expression of NRG1 (p = 0.026, p < 0.001, p < 0.001), ErbB4 (p < 0.001, p < 0.001, p < 0.001) and Gata4 (p = 0.014, p < 0.001, p = 0.006) in groups E, M and ME increased significantly, while C/EBPß decreased significantly (p < 0.001, p = 0.001, p = 0.002). SIGNIFICANCE: Our findings suggest that MOTS-c and aerobic exercise had similar effects, improving myocardial morphology and structure and enhancing cardiac function through activation of the NRG1-ErbB4-C/EBPß pathway.

MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling in Diabetic Rats.

Pathologic cardiac remodeling and dysfunction are the most common complications of type 2 diabetes. Physical exercise is important in inhibiting myocardial pathologic remodeling and restoring cardiac function in diabetes. The mitochondrial-derived peptide MOTS-c has exercise-like effects by improving insulin resistance, combatting hyperglycemia, and reducing lipid accumulation. We investigated the effects and transcriptomic profiling of MOTS-c and aerobic exercise on cardiac properties in a rat model of type 2 diabetes which was induced by feeding a high fat high sugar diet combined with an injection of a low dose of streptozotocin. Both aerobic exercise and MOTS-c treatment reduced abnormalities in cardiac structure and function. Transcriptomic function enrichment analysis revealed that MOTS-c had exercise-like effects on inflammation, myocardial apoptosis, angiogenesis and endothelial cell proliferation and migration, and showed that the NRG1-ErbB4 pathway might be an important component in both MOTS-c and exercise induced attenuation of cardiac dysfunction in diabetes. Moreover, our findings suggest that MOTS-c activates NRG1-ErbB4 signaling and mimics exercise-induced cardio-protection in diabetes.

An HDAC6 inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway.

Chemotherapy-induced peripheral neuropathy (CIPN) impacts a growing number of cancer survivors and treatment options are limited. Histone deacetylase 6 (HDAC6) inhibitors are attractive candidates because they reverse established CIPN and may enhance anti-tumor effects of chemotherapy. Before considering clinical application of HDAC6 inhibitors, the mechanisms underlying reversal of CIPN need to be identified. We showed previously that deletion of Hdac6 from sensory neurons did not prevent cisplatin-induced mechanical hypersensitivity, while global deletion of Hdac6 was protective, indicating involvement of HDAC6 in other cell types. Here we show that local depletion of MRC1 (CD206)-positive macrophages without affecting microglia by intrathecal administration of mannosylated clodronate liposomes reduced the capacity of an HDAC6 inhibitor to reverse cisplatin-induced mechanical hypersensitivity. The HDAC6 inhibitor increased spinal cord Il10 mRNA and this was M2-macrophage dependent. Intrathecal administration of anti-IL-10 antibody or genetic deletion of Il10 prevented resolution of mechanical hypersensitivity. Genetic deletion of the IL-10 receptor from Advillin+ neurons prevented resolution of mechanical hypersensitivity in mice treated with the HDAC6 inhibitor. These findings indicate that treatment with an HDAC6 inhibitor increases macrophage-derived IL-10 signaling to IL-10 receptors on Advillin+ sensory neurons to resolve mechanical hypersensitivity. Cisplatin decreases mitochondrial function in sensory axons, and HDAC6 inhibition can promote axonal transport of healthy mitochondria. Indeed, the HDAC6 inhibitor normalized cisplatin-induced tibial nerve mitochondrial deficits. However, this was independent of macrophages and IL-10 signaling. In conclusion, our findings indicate that administration of an HDAC6 inhibitor reverses cisplatin-induced mechanical hypersensitivity through two complementary pathways: macrophage HDAC6 inhibition to promote IL-10 production and IL-10 signaling to DRG neurons, and neuronal HDAC6 inhibition to restore axonal mitochondrial health.

TTI-101: A competitive inhibitor of STAT3 that spares oxidative phosphorylation and reverses mechanical allodynia in mouse models of neuropathic pain.

Signal Transducer and Activator of Transcription (STAT) 3 emerged rapidly as a high-value target for treatment of cancer. However, small-molecule STAT3 inhibitors have been slow to enter the clinic due, in part, to serious adverse events (SAE), including lactic acidosis and peripheral neuropathy, which have been attributed to inhibition of STAT3's mitochondrial function. Our group developed TTI-101, a competitive inhibitor of STAT3 that targets the receptor pY705-peptide binding site within the Src homology 2 (SH2) domain to block its recruitment and activation. TTI-101 has shown target engagement, no toxicity, and evidence of clinical benefit in a Phase I study in patients with solid tumors. Here we report that TTI-101 did not affect mitochondrial function, nor did it cause STAT3 aggregation, chemically modify STAT3 or cause neuropathic pain. Instead, TTI-101 unexpectedly suppressed neuropathic pain induced by chemotherapy or in a spared nerve injury model. Thus, in addition to its direct anti-tumor effect, TTI-101 may be of benefit when administered to cancer patients at risk of developing chemotherapy-induced peripheral neuropathy (CIPN).

Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments.

ABSTRACT: Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-approved agents for the prevention or curative treatment of CIPN or CICI. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration that is localized to axons and coordinates the neuronal response to injury. We developed a novel brain-penetrant DLK inhibitor, IACS'8287, which demonstrates potent and highly selective inhibition of DLK in vitro and in vivo. Coadministration of IACS'8287 with the platinum derivative cisplatin prevents mechanical allodynia, loss of intraepidermal nerve fibers in the hind paws, cognitive deficits, and impairments in brain connectivity in mice, all without interfering with the antitumor activity of cisplatin. The protective effects of IACS'8287 are associated with preservation of mitochondrial function in dorsal root ganglion neurons and in brain synaptosomes. In addition, RNA sequencing analysis of dorsal root ganglia reveals modulation of genes involved in neuronal activity and markers for immune cell infiltration by DLK inhibition. These data indicate that CIPN and CICI require DLK signaling in mice, and DLK inhibitors could become an attractive treatment in the clinic when coadministered with cisplatin, and potentially other chemotherapeutic agents, to prevent neurotoxicities as a result of cancer treatment.

Crown Ether Functionalized Potassium-Responsive Anionocages for Cascaded Guest Delivery.

In many critical biological processes, host-guest chemistry of protein receptors is regulated by effector molecules to realize cascaded delivery of messenger molecules between different targets. Mimicking these natural processes with artificial receptors remains a challenge. Herein, we report a cascaded guest delivery between two anionocages (anion-coordination-driven cages), in a reversible manner, wherein binding of K+ ions by a crown ether functionalized, heteroleptic A2 L3 (A=anion, L=ligand) anionocage triggers the release and delivery of a TEA+ (tetraethylammonium) guest to another A2 L3 anionocage that is a weaker and less K+ -sensitive receptor. Elimination of the K+ with [2,2,2]-cryptand enables recapture of the TEA+ by the crown ether functionalized anionocage and thus realizes a reversed guest delivery. Moreover, integrative self-sorting of anionocages is firstly reported, leading to heteroleptic cages with enhanced guest binding affinities.

Nasal administration of mesenchymal stem cells reverses chemotherapy-induced peripheral neuropathy in mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequently reported adverse effects of cancer treatment. CIPN often persists long after treatment completion and has detrimental effects on patient's quality of life. There are no efficacious FDA-approved drugs for CIPN. We recently demonstrated that nasal administration of mesenchymal stem cells (MSC) reverses the cognitive deficits induced by cisplatin in mice. Here we show that nasal administration of MSC after cisplatin- or paclitaxel treatment- completely reverses signs of established CIPN, including mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. Nasally administered MSC enter rapidly the meninges of the brain, spinal cord and peripheral lymph nodes to promote IL-10 production by macrophages. MSC-mediated resolution of mechanical allodynia, recovery of IENFs and restoration of DRG mitochondrial function critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, WT MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons. In conclusion, only two nasal administrations of MSC fully reverse CIPN and the associated mitochondrial abnormalities via an IL-10 dependent pathway. Since MSC are already applied clinically, we propose that nasal MSC treatment could become a powerful treatment for the large group of patients suffering from neurotoxicities of cancer treatment.

Oral Dimethyl Fumarate Reduces Peripheral Neuropathic Pain in Rodents via NFE2L2 Antioxidant Signaling.

BACKGROUND: Available treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic node for neuropathic pain, the authors focused on the master regulator of the antioxidant response-nuclear factor erythroid 2-related factor 2 (NFE2L2; Nrf2)-as an alternative target for neuropathic pain. The authors tested whether dimethyl fumarate (U.S. Food and Drug Administration-approved treatment for multiple sclerosis) would activate NFE2L2 and promote antioxidant activity to reverse neuropathic pain behaviors and oxidative stress-dependent mechanisms. METHODS: Male Sprague Dawley rats, and male and female wild type and Nfe2l2 mice were treated with oral dimethyl fumarate/vehicle for 5 days (300 mg/kg; daily) after spared nerve injury/sham surgery (n = 5 to 8 per group). Allodynia was measured in von Frey reflex tests and hyperalgesia in operant conflict-avoidance tests. Ipsilateral L4/5 dorsal root ganglia were assayed for antioxidant and cytokine/chemokine levels, and mitochondrial bioenergetic capacity. RESULTS: Dimethyl fumarate treatment reversed mechanical allodynia (injury-vehicle, 0.45 ± 0.06 g [mean ± SD]; injury-dimethyl fumarate, 8.2 ± 0.16 g; P < 0.001) and hyperalgesia induced by nerve injury (injury-vehicle, 2 of 6 crossed noxious probes; injury-dimethyl fumarate, 6 of 6 crossed; P = 0.013). The antiallodynic effect of dimethyl fumarate was lost in nerve-injured Nfe2l2 mice, but retained in nerve-injured male and female wild type mice (wild type, 0.94 ± 0.25 g; Nfe2l2, 0.02 ± 0.01 g; P < 0.001). Superoxide dismutase activity was increased by dimethyl fumarate after nerve injury (injury-vehicle, 3.96 ± 1.28 mU/mg; injury-dimethyl fumarate, 7.97 ± 0.47 mU/mg; P < 0.001). Treatment reduced the injury-dependent increases in cytokines and chemokines, including interleukin-1ß (injury-vehicle, 13.30 ± 2.95 pg/mg; injury-dimethyl fumarate, 6.33 ± 1.97 pg/mg; P = 0.022). Injury-impaired mitochondrial bioenergetics, including basal respiratory capacity, were restored by dimethyl fumarate treatment (P = 0.025). CONCLUSIONS: Dimethyl fumarate, a nonopioid and orally-bioavailable drug, alleviated nociceptive hypersensitivity induced by peripheral nerve injury via activation of NFE2L2 antioxidant signaling. Dimethyl fumarate also resolved neuroinflammation and mitochondrial dysfunction-oxidative stress-dependent mechanisms that drive nociceptive hypersensitivity after nerve injury.

Cell-specific role of histone deacetylase 6 in chemotherapy-induced mechanical allodynia and loss of intraepidermal nerve fibers.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of cancer treatment with no Food and Drug Administration-approved medication for its prevention or management. Using RNA sequencing analysis of dorsal root ganglia (DRG), we identify critical contributions of histone deacetylase 6 (HDAC6) and mitochondrial damage to the establishment of CIPN in a mouse model of cisplatin-induced neuropathy. We show that pharmacological inhibition of HDAC6 using ACY-1215 or global deletion of HDAC6 is sufficient to prevent cisplatin-induced mechanical allodynia, loss of intraepidermal nerve fibers (IENFs), and mitochondrial bioenergetic deficits in DRG neurons and peripheral nerves in male and female mice. The bioenergetic deficits in the neuronal cell bodies in the DRG are characterized by reduced oxidative phosphorylation, whereas the mitochondrial deficits in the nerves are due to a reduction in axonal mitochondrial content. Notably, deleting HDAC6 in sensory neurons protects against the cisplatin-induced loss of IENFs and the reduction in mitochondrial bioenergetics and content in the peripheral nerve. By contrast, deletion of HDAC6 in sensory neurons only partially and transiently prevents cisplatin-induced mechanical allodynia and does not protect against impairment of mitochondrial function in DRG neurons. We further reveal a critical role of T cells in the protective effects of HDAC6 inhibition on these signs of CIPN. In summary, we show that cisplatin-induced mechanical allodynia is associated with mitochondrial damage in DRG neurons, whereas the loss of IENFs is related to bioenergetic deficits in peripheral nerves. Moreover, our findings identify cell-specific contributions of HDAC6 to mechanical allodynia and loss of IENFs that characterize cisplatin-induced peripheral neuropathy.

Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment.

Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients' daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairments in male mice, as demonstrated in the Y-maze test of spontaneous alternation, the novel object/place recognition test, and the puzzle box test. Normalization of cognitive impairment was associated with reversal of cisplatin-induced synaptosomal mitochondrial deficits and restoration of synaptic integrity. Mechanistically, cisplatin induced deacetylation of the microtubule protein α-tubulin and hyperphosphorylation of the microtubule-associated protein tau. These cisplatin-induced changes were reversed by HDAC6 inhibition. Our data suggest that inhibition of HDAC6 restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptosomal mitochondrial function and synaptic integrity and thereby to reversal of CICI. Remarkably, our results indicate that short-term daily treatment with the HDAC6 inhibitor was sufficient to achieve prolonged reversal of established behavioral, structural and functional deficits induced by cisplatin. Because the beneficial effects of HDAC6 inhibitors as add-ons to cancer treatment have been demonstrated in clinical trials, selective targeting of HDAC6 with brain-penetrating inhibitors appears a promising therapeutic approach for reversing chemotherapy-induced neurotoxicity while enhancing tumor control.

Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is important to note that such interventions should not interfere with the antitumor effects of chemotherapy. Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy "currency" adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Herein, the authors discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-µ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system. Cancer 2018;124:2289-98. © 2018 American Cancer Society.

Inhibition of Mitochondrial p53 Accumulation by PFT-µ Prevents Cisplatin-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN), a debilitating major side effect of cancer treatment, is characterized by pain and sensory loss in hand and feet. Platinum-based chemotherapeutics like cisplatin frequently induce CIPN. The molecular mechanism underlying these neurotoxic symptoms is incompletely understood and there are no preventive or curative interventions. We hypothesized that cisplatin acts as a cellular stressor that triggers p53 accumulation at mitochondria, leading to mitochondrial dysfunction and CIPN. To test this hypothesis, we examined the effect of the small molecule pifithrin-µ (PFT-µ), an inhibitor of p53 mitochondrial association on CIPN and the associated mitochondrial dysfunction. We show here for the first time that in vivo cisplatin rapidly increases mitochondrial accumulation of p53 in dorsal root ganglia (DRG), spinal cord, and peripheral nerve without evidence for apoptosis. Cisplatin-treatment also reduced mitochondrial membrane potential and lead to abnormal mitochondrial morphology and impaired mitochondrial function in DRG neurons. Pre-treatment with PFT-µ prevented the early cisplatin-induced increase in mitochondrial p53 and the reduction in mitochondrial membrane potential. Inhibition of the early mitochondrial p53 accumulation by PFT-µ also prevented the abnormalities in mitochondrial morphology and mitochondrial bioenergetics (reduced oxygen consumption rate, maximum respiratory capacity, and adenosine triphosphate synthesis) that develop in DRG and peripheral nerve after cisplatin-treatment. Functionally, inhibition of mitochondrial p53 accumulation prevented the hallmarks of CIPN including mechanical allodynia, peripheral sensory loss (numbness) as quantified by an adhesive-removal task, and loss of intra-epidermal nerve fibers. In conclusion, PFT-µ is a potential neuroprotective agent that prevents cisplatin-induced mitochondrial dysfunction in DRG and peripheral nerves thereby protecting against CIPN through blockade of the early cisplatin-induced increase in mitochondrial p53. Notably, there is accumulating evidence that PFT-µ has anti-tumor activities and could therefore be an attractive candidate to prevent CIPN while promoting tumor cell death.

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin-dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.

Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail.

Novobiocin is a natural product that binds the Hsp90 C-terminus and manifests Hsp90 inhibitory activity. Structural investigations on novobiocin led to the development of both anti-cancer and neuroprotective agents. The varied pharmacological activity manifested by these novobiocin analogs prompted the investigation of structure-function studies to identify these contradictory effects, which revealed that modifications to the amide side chain produce either anti-cancer or neuroprotective activity. Compounds that exhibit neuroprotective activity contain a short alkyl or cycloalkyl amide side chain. In contrast, anti-cancer agents contain five or more carbons, disrupt interactions between Hsp90α and Aha1, and induce the degradation of Hsp90-dependent client proteins.

Recurrent and pathological gene fusions in breast cancer: current advances in genomic discovery and clinical implications.

Gene fusions have long been considered principally as the oncogenic events of hematologic malignancies, but have recently gained wide attention in solid tumors due to several milestone discoveries and the advancement of deep sequencing technologies. With the progress in deep sequencing studies of breast cancer transcriptomes and genomes, the discovery of recurrent and pathological gene fusions in breast cancer is on the focus. Recently, driven by new deep sequencing studies, several recurrent or pathological gene fusions have been identified in breast cancer, including ESR1-CCDC170, SEC16A-NOTCH1, SEC22B-NOTCH2, and ESR1-YAP1 etc. More important, most of these gene fusions are preferentially identified in the more aggressive breast cancers, such as luminal B, basal-like, or endocrine-resistant breast cancer, suggesting recurrent gene fusions as additional key driver events in these tumors other than the known drivers such as the estrogen receptor. In this paper, we have comprehensively summarized the newly identified recurrent or pathological gene fusion events in breast cancer, reviewed the contributions of new genomic and deep sequencing technologies to new fusion discovery and the integrative bioinformatics tools to analyze these data, highlighted the biological relevance and clinical implications of these fusion discoveries, and discussed future directions of gene fusion research in breast cancer.