{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T20:35:30Z","timestamp":1783110930399,"version":"3.54.6"},"reference-count":79,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health of Ukraine","award":["BH.14.01.07.204-23"],"award-info":[{"award-number":["BH.14.01.07.204-23"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Osteosarcoma (OS) is the most common primary malignant bone tumor. Doxorubicin (DOX) is extensively used in OS chemotherapy, yet improving patient outcomes remains challenging. This study investigated the effect of free DOX combined with inductive moderate hyperthermia (IMH) on Saos-2 human OS cells. Methods: Cell viability was assessed by trypan blue exclusion. Flow cytometry analyzed apoptosis, necrosis, and reactive oxygen species (ROS) in cells exposed to control (no treatment), IMH (42 MHz frequency, 500 \u03bcT magnetic field induction, 564 V\/m electric field strength, 15 W output power, and 30 min duration) alone, DOX (0.06 \u03bcg\/mL) alone, or DOX combined with IMH. The expression of p14ARF tumor suppressor and epidermal growth factor receptor (EGFR) was evaluated by immunocytochemistry. Spatial autocorrelation analysis quantified the heterogeneity of p14ARF and EGFR distributions in acquired images. Results: The half maximal inhibitory concentration (IC50) of DOX in Saos-2 cells had minimal variation between 48 h (0.060 \u00b1 0.01 \u03bcg\/mL) and 72 h (0.055 \u00b1 0.003 \u03bcg\/mL). DOX + IMH resulted in a 15% increase in early apoptosis and a 20% elevation in ROS levels compared with DOX alone. Immunocytochemical analysis revealed a 37% increase in p14ARF and a 32% reduction in EGFR expression following combined treatment in comparison to DOX alone. Image analysis showed that DOX + IMH treatment caused the highest Moran\u2019s index values for p14ARF and EGFR, reflecting less heterogeneous spatial distributions (p &lt; 0.05). Conclusions: IMH enhanced DOX-induced cytotoxicity in Saos-2 cells by initiating ROS-mediated apoptosis and reducing heterogeneity of cellular responses.<\/jats:p>","DOI":"10.3390\/ph18060852","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T11:08:31Z","timestamp":1749208111000},"page":"852","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Combination Treatment with Free Doxorubicin and Inductive Moderate Hyperthermia for Sarcoma Saos-2 Cells"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6319-4215","authenticated-orcid":false,"given":"Valerii E.","family":"Orel","sequence":"first","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"},{"name":"National Technical University of Ukraine \u201cIgor Sikorsky Kyiv Polytechnic Institute\u201d, 16\/2 Yangel Str., 03056 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2187-0502","authenticated-orcid":false,"given":"Anatolii G.","family":"Diedkov","sequence":"additional","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5409-5194","authenticated-orcid":false,"given":"Vasyl V.","family":"Ostafiichuk","sequence":"additional","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergii A.","family":"Lyalkin","sequence":"additional","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor O.","family":"Tkachenko","sequence":"additional","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denys L.","family":"Kolesnyk","sequence":"additional","affiliation":[{"name":"R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, 45 Vasylkivska Str., 03022 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3653-0823","authenticated-orcid":false,"given":"Valerii B.","family":"Orel","sequence":"additional","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"},{"name":"National Technical University of Ukraine \u201cIgor Sikorsky Kyiv Polytechnic Institute\u201d, 16\/2 Yangel Str., 03056 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga Yo.","family":"Dasyukevich","sequence":"additional","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleksandr Yu.","family":"Rykhalskyi","sequence":"additional","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2874-8841","authenticated-orcid":false,"given":"Oleksii V.","family":"Movchan","sequence":"additional","affiliation":[{"name":"National Cancer Institute, 33\/43 Zdanovska Str., 03022 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Yu.","family":"Galkin","sequence":"additional","affiliation":[{"name":"National Technical University of Ukraine \u201cIgor Sikorsky Kyiv Polytechnic Institute\u201d, 16\/2 Yangel Str., 03056 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna B.","family":"Prosvietova","sequence":"additional","affiliation":[{"name":"National Technical University of Ukraine \u201cIgor Sikorsky Kyiv Polytechnic Institute\u201d, 16\/2 Yangel Str., 03056 Kyiv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41572-022-00409-y","article-title":"Osteosarcoma","volume":"8","author":"Beird","year":"2022","journal-title":"Nat. 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