{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:02:29Z","timestamp":1787029349908,"version":"build-2736575974"},"reference-count":287,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Republic of Serbia, Autonomous Province of Vojvodina, Provincial Secretariat for High Education and Scientific Research","award":["003877305 2025 09418 003 000 000 001 04 004"],"award-info":[{"award-number":["003877305 2025 09418 003 000 000 001 04 004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: In previous studies, chloroquine and ivermectin separately exhibited similar anticancer effects on various known cancer modulatory targets. This study aimed (1) to identify a non-toxic synergistic combination of chloroquine and ivermectin that suppresses hamster fibrosarcoma; (2) to verify combined antitumor efficacy using dose\u2013response analysis; and (3) to investigate potential synergistic mechanisms by restoring tumor progression with the reciprocal cancer-modulating agent deoxycholic acid. Methods: A BHK-21\/C13 cell culture was subcutaneously inoculated into Syrian golden hamsters randomly divided into groups (6 animals per group): (1) untreated control; treated daily (17 days after inoculation) with (2) chloroquine 50 mg\/kg; (3) ivermectin 5 mg\/kg; (4) a combination of chloroquine 50 mg\/kg and ivermectin 5 mg\/kg; (5) a combination of chloroquine 50 mg\/kg, ivermectin 5 mg\/kg and deoxycholic acid 100 mg\/kg; (6) a combination of chloroquine 25 mg\/kg and ivermectin 2.5 mg\/kg; (7) a combination of chloroquine 12.5 mg\/kg and ivermectin 1.25 mg\/kg. Dose\u2013response curves were generated for chloroquine and ivermectin combinations. Characteristics of tumors (growth kinetics, biophysical, histological, immunohistochemical, pathological), hamster organs, biochemical and hematological blood tests were compared among the groups. Results: The synergistic, dose-dependent anticancer effects of two antiparasitic agents, similar tumor-regulation modulators chloroquine and ivermectin, in doses equivalent to human doses were observed in fibrosarcoma in hamsters (both drugs approximately 1\/10 LD50) without toxicity and in various cell lines of human lung, colon and cervical carcinomas and hamster fibrosarcoma in vitro. The addition of a reciprocal modulator of cancer regulation, NF-\u03baB stimulator deoxycholic acid, caused a huge rescue effect on fibrosarcoma and a reversal of the successful anticancer therapy using the combination. Conclusions: The chloroquine and ivermectin combination may be recommended for comprehensive additional preclinical and clinical evaluation due to its synergistic anticancer effects. Further preclinical and clinical exploration will be crucial to thoroughly define the optimal role of the combination therapy in the treatment of fibrosarcoma and potentially other cancer types.<\/jats:p>","DOI":"10.3390\/ph19030407","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T16:06:59Z","timestamp":1772467619000},"page":"407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Captivating Synergistic, Dose-Dependent Anticancer Effects of Tumor-Regulation Modulators Chloroquine and Ivermectin Completely Abolished by an Opposing Modulator, Deoxycholic Acid, in Hamster Fibrosarcoma: In Vivo, In Vitro, and Literature Review"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7895-9009","authenticated-orcid":false,"given":"Kosta J.","family":"Popovi\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7880-0874","authenticated-orcid":false,"given":"Du\u0161ica J.","family":"Popovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, State University of Novi Pazar, Vuka Karad\u017ei\u0107a 9, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7739-5202","authenticated-orcid":false,"given":"Dejan","family":"Miljkovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6790-8668","authenticated-orcid":false,"given":"Jovan K.","family":"Popovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia"},{"name":"Academy of Medical Sciences of the Serbian Medical Society, 19 George Washington Str., 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8044-2655","authenticated-orcid":false,"given":"Mihalj","family":"Po\u0161a","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovana","family":"Drlja\u010da Lero","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0457-3087","authenticated-orcid":false,"given":"Zana","family":"Doli\u0107anin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, State University of Novi Pazar, Vuka Karad\u017ei\u0107a 9, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,1]]},"reference":[{"key":"ref_1","unstructured":"Kesharwani, P., and Gupta, N. 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