α-Phellandrene exhibits antinociceptive and tumor-reducing effects in a mouse model of oncologic pain

• Published in: Toxicology and applied pharmacology Vol. 418; p. 115497
• Main Authors: Pinheiro-Neto, Flaviano Ribeiro, Lopes, Everton Moraes, Acha, Boris Timah, Gomes, Laércio da Silva, Dias, Willian Amorim, Reis Filho, Antonio Carlos dos, Leal, Bianca de Sousa, Rodrigues, Débora Caroline do Nascimento, Silva, Jurandy do Nascimento, Dittz, Dalton, Ferreira, Paulo Michel Pinheiro, Almeida, Fernanda Regina de Castro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2021
• Subjects: Adjuvant therapy; Analgesics - pharmacology; Animals; Antineoplastic Agents - pharmacology; Cancer Pain - drug therapy; Cancer Pain - etiology; Cancer Pain - metabolism; Cancer-related allodynia; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclohexane Monoterpenes - pharmacology; Cytokines - metabolism; Female; Glutathione - metabolism; Inflammation Mediators - metabolism; Interleukins; Lipid Peroxidation - drug effects; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Monoterpenes; Pain Threshold; Sarcoma 180; Sarcoma 180 - complications; Sarcoma 180 - drug therapy; Sarcoma 180 - metabolism; Sarcoma 180 - pathology; Tumor Burden - drug effects; Tumor Cells, Cultured; Monoterpenes; Interleukins; Sarcoma 180; Cancer-related allodynia; Adjuvant therapy
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2021.115497

Medical reports indicate a prevalence of pain in 50% of patients with cancer. In this context, this article investigated the antinociceptive activity of α-PHE using in vivo Sarcoma-180-induced hypernociception in mice to detail its mechanism(s) of antinociception under different conditions of treatment and tumor progression. Firsty, in vitro cytotoxic action was assessed using melanoma B-16/F-10 and S-180 murine cells and colorimetric MTT assays. For in vivo studies, acute treatment with α-PHE (6.25, 12.5, 25 and 50 mg/kg orally by gavage) was performed on the 1st day after S-180 inoculation. Subacute treatments were performed for 8 days starting on the next day (early protocol) or on day 8 after S-180 inoculation (late protocol). For all procedures, mechanical nociceptive evaluations were carried out by von Frey's technique in the subaxillary region peritumoral tissue (direct nociception) and in right legs of S-180-bearing mice (indirect nociception). α-PHE showed in vitro cytotoxic action on B-16/F-10 and S-180 (CI50 values of 436.0 and 217.9 μg/mL), inhibition of in vivo tumor growth (ranging from 47.3 to 82.7%) and decreased direct (peritumoral tissue in subaxillary region) and indirect (right leg) mechanical nociception in Sarcoma 180-bearing mice with early and advanced tumors under acute or subacute conditions of treatment especially at doses of 25 and 50 mg/kg. It improved serum levels of GSH as well as diminished systemic lipid peroxidation, blood cytokines (interleukin-1β, −4, −6, and tumor necrosis factor-α). Such outcomes highlight α-PHE as a promising lead compound that combines antinociceptive and antineoplasic properties. Its structural simplicity make it a cost-effective alternative, justifying further mechanistic investigations and the development of pharmaceutical formulations. Moreover, the protocols developed and standardized here make it possible to use Sarcoma-180 hypernociception model to evaluate the capacity of new antinociceptive molecules under conditions of cancer-related allodynia.
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•α-PHE showed antiallodynic effects in Sarcoma 180-bearing mice in mimetic animal models of early/advanced cancers.•It presented amazing antitumor capacity, which is independent of the antinociceptive action.•Its chemopreventive action decreased in vivo lipid peroxidation and improved GSH concentration.•α-PHE reduced the levels of pro-inflammatory cytokines.•Antinociceptive effects of α-PHE against oncologic pain involves GABAergic and opioid systems.