Cancer Pain: From Basic Research to Drug Discovery and Clinical Studies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Survivorship and Quality of Life".

Deadline for manuscript submissions: closed (20 March 2024) | Viewed by 9032

Special Issue Editors


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Guest Editor
Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, Budapest, Hungary
Interests: the capsaicin (vanilloid) receptor TRPV1; “thermoTRP” expression in cancer; TRP channels as oncotargets; TRP channels as tumor suppressors; sensory nerve-tumor interactions; oncothermia
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Physiology and Pharmacology, Health Sciences Center, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
Interests: pharmacology of pain; analgesics; TRP channels; TRPA1; TRPV1
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
National Institute of Oncology, Pain Management Outpatient Clinic, 1122 Budapest, Hungary
Interests: cancer pain management

Special Issue Information

Dear Colleagues,

Cancer pain is one of the worst forms of chronic pain, with opioids being the mainstay of treatment. Unfortunately, most patients quickly develop opioid tolerance, leaving them with few therapeutic alternatives while battling this deadly disease. Thus, there is an urgent need to identify molecular mechanisms driving cancer pain to develop novel analgesic drugs. Most cancer pain occurs when the tumor destroys tissues or presses on nerves. However, cancer cells can also produce substances that make normally innocuous stimuli feel painful. Furthermore, therapeutic interventions can induce pain as an adverse effect, as exemplified by chemotherapy-induced peripheral neuropathy.

With this Special Issue, we aim to explore the current state of the cancer pain field, from basic research through to drug discovery and the development to clinical trials. Original research papers, reviews, clinical studies, and meta-analyses of clinical trials are all welcome to contribute.

Dr. Arpad Szallasi
Prof. Dr. Gabriela Trevisan
Dr. Andreea Dumele
Guest Editors

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Published Papers (5 papers)

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Research

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17 pages, 2769 KiB  
Article
Osteosarcoma-Induced Pain Is Mediated by Glial Cell Activation in the Spinal Dorsal Horn, but Not Capsaicin-Sensitive Nociceptive Neurons: A Complex Functional and Morphological Characterization in Mice
by Noémi Bencze, Bálint Scheich, Éva Szőke, Imola Wilhelm, Sándor Körmöndi, Bálint Botz and Zsuzsanna Helyes
Cancers 2024, 16(10), 1788; https://doi.org/10.3390/cancers16101788 - 7 May 2024
Viewed by 1240
Abstract
Bone cancer and its related chronic pain are huge clinical problems since the available drugs are often ineffective or cannot be used long term due to a broad range of side effects. The mechanisms, mediators and targets need to be identified to determine [...] Read more.
Bone cancer and its related chronic pain are huge clinical problems since the available drugs are often ineffective or cannot be used long term due to a broad range of side effects. The mechanisms, mediators and targets need to be identified to determine potential novel therapies. Here, we characterize a mouse bone cancer model induced by intratibial injection of K7M2 osteosarcoma cells using an integrative approach and investigate the role of capsaicin-sensitive peptidergic sensory nerves. The mechanical pain threshold was assessed by dynamic plantar aesthesiometry, limb loading by dynamic weight bearing, spontaneous pain-related behaviors via observation, knee diameter with a digital caliper, and structural changes by micro-CT and glia cell activation by immunohistochemistry in BALB/c mice of both sexes. Capsaicin-sensitive peptidergic sensory neurons were defunctionalized by systemic pretreatment with a high dose of the transient receptor potential vanilloid 1 (TRPV1) agonist resiniferatoxin (RTX). During the 14- and 28-day experiments, weight bearing on the affected limb and the paw mechanonociceptive thresholds significantly decreased, demonstrating secondary mechanical hyperalgesia. Signs of spontaneous pain and osteoplastic bone remodeling were detected both in male and female mice without any sex differences. Microglia activation was shown by the increased ionized calcium-binding adapter molecule 1 (Iba1) immunopositivity on day 14 and astrocyte activation by the enhanced glial fibrillary acidic protein (GFAP)-positive cell density on day 28 in the ipsilateral spinal dorsal horn. Interestingly, defunctionalization of the capsaicin-sensitive afferents representing approximately 2/3 of the nociceptive fibers did not alter any functional parameters. Here, we provide the first complex functional and morphological characterization of the K7M2 mouse osteosarcoma model. Bone-cancer-related chronic pain and hyperalgesia are likely to be mediated by central sensitization involving neuroinflammation via glial cell activation in the spinal dorsal horn, but not the capsaicin-sensitive sensory neuronal system. Full article
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10 pages, 1294 KiB  
Article
Methylene Blue for the Treatment of Radiation-Induced Oral Mucositis during Head and Neck Cancer Treatment: An Uncontrolled Cohort
by Carlos J. Roldan, David I. Rosenthal, Dhanalakshmi Koyyalagunta, Lei Feng and Keith Warner
Cancers 2023, 15(15), 3994; https://doi.org/10.3390/cancers15153994 - 7 Aug 2023
Cited by 1 | Viewed by 1653
Abstract
Pain from radiation-therapy-induced oral mucositis during head-neck cancer treatment is aggravated by concurrent chemotherapy and commonly fails traditional treatments. To explore safe and sustainable alternatives, we investigated methylene blue oral rinse to reduce radiation-therapy-related oral mucositis pain. For this, we conducted a retrospective [...] Read more.
Pain from radiation-therapy-induced oral mucositis during head-neck cancer treatment is aggravated by concurrent chemotherapy and commonly fails traditional treatments. To explore safe and sustainable alternatives, we investigated methylene blue oral rinse to reduce radiation-therapy-related oral mucositis pain. For this, we conducted a retrospective observational cohort study in a tertiary-care academic care cancer center including 85 patients with refractory oral mucositis pain during radiation therapy for head-neck cancer. Changes in pain (scale 0–10), oral function burden (scale 0–6) and requirement for percutaneous endoscopic gastrostomy tube placement were measured. Among 58 patients, 60% received radiation therapy alone and 40% received concurrent chemotherapy-radiation therapy. Methylene blue oral rinse (MBOR) significantly decreased oral mucositis pain for at least 6.2 h (median + SD 8 ± 1.68 before vs. 2 ± 2.20 after; p < 0.0001) and oral function burden (3.5 ± 1.33 before vs. 0 ± 0.86 after; p < 0.0001). Eleven patients (19%) had percutaneous endoscopic gastrostomy tubes placed before using methylene blue oral rinse; subsequently, four (36%) resumed oral alimentation after methylene blue oral rinse. Two patients (3%) required percutaneous endoscopic gastrostomy tubes despite methylene blue oral rinse. Minimal adverse events were reported (n = 9, 15%). Our study showed that methylene blue oral rinse was an effective and safe topical treatment for opioid-refractory oral pain from oral mucositis associated with radiation therapy for head-neck cancer. Full article
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Review

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23 pages, 1743 KiB  
Review
Targeting TRPV4 Channels for Cancer Pain Relief
by Caren Tatiane de David Antoniazzi, Náthaly Andrighetto Ruviaro, Diulle Spat Peres, Patrícia Rodrigues, Fernanda Tibolla Viero and Gabriela Trevisan
Cancers 2024, 16(9), 1703; https://doi.org/10.3390/cancers16091703 - 27 Apr 2024
Cited by 1 | Viewed by 1491
Abstract
Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This [...] Read more.
Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels’ involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics. Full article
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20 pages, 2408 KiB  
Review
Targeting TRPV1 for Cancer Pain Relief: Can It Work?
by Arpad Szallasi
Cancers 2024, 16(3), 648; https://doi.org/10.3390/cancers16030648 - 2 Feb 2024
Cited by 2 | Viewed by 2374
Abstract
Chronic intractable pain affects a large proportion of cancer patients, especially those with metastatic bone disease. Blocking sensory afferents for cancer pain relief represents an attractive alternative to opioids and other drugs acting in the CNS in that sensory nerve blockers are not [...] Read more.
Chronic intractable pain affects a large proportion of cancer patients, especially those with metastatic bone disease. Blocking sensory afferents for cancer pain relief represents an attractive alternative to opioids and other drugs acting in the CNS in that sensory nerve blockers are not addictive and do not affect the mental state of the patient. A distinct subpopulation of sensory afferents expresses the capsaicin receptor TRPV1. Intrathecal resiniferatoxin, an ultrapotent capsaicin analog, ablates TRPV1-expressing nerve endings exposed to the cerebrospinal fluid, resulting in permanent analgesia in women with cervical cancer metastasis to the pelvic bone. High-dose capsaicin patches are effective pain killers in patients with chemotherapy-induced peripheral neuropathic pain. However, large gaps remain in our knowledge since the mechanisms by which cancer activates TRPV1 are essentially unknown. Most important, it is not clear whether or not sensory denervation mediated by TRPV1 agonists affects cancer progression. In a murine model of breast cancer, capsaicin desensitization was reported to accelerate progression. By contrast, desensitization mediated by resiniferatoxin was found to block melanoma growth. These observations imply that TRPV1 blockade for pain relief may be indicated for some cancers and contraindicated for others. In this review, we explore the current state of this field and compare the analgesic potential of TRPV1 antagonism and sensory afferent desensitization in cancer patients. Full article
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18 pages, 3531 KiB  
Review
G Protein-Coupled Receptors and Ion Channels Involvement in Cisplatin-Induced Peripheral Neuropathy: A Review of Preclinical Studies
by Gabriela Becker, Samuel Felipe Atuati and Sara Marchesan Oliveira
Cancers 2024, 16(3), 580; https://doi.org/10.3390/cancers16030580 - 30 Jan 2024
Cited by 3 | Viewed by 1682
Abstract
Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system [...] Read more.
Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system and is a significant cause of debilitation and suffering in patients. In recent years, preclinical studies have been conducted to elucidate the mechanisms involved in chemotherapy-induced peripheral neuropathic pain, as well as to promote new therapeutic targets since current treatments are ineffective and are associated with adverse effects. G-protein coupled receptors and ion channels play a significant role in pain processing and may represent promising targets for improving the management of cisplatin-induced neuropathic pain. This review describes the role of G protein-coupled receptors and ion channels in cisplatin-induced pain, analysing preclinical experimental studies that investigated the role of each receptor subtype in the modulation of cisplatin-induced pain. Full article
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