Evaluation of the antitumor efficacy of doxorubicin in monotherapy and in combination with a HIF-1α inhibitor in a vivo model of hepatocellular carcinoma

In our work, we attempted to improve the antitumor efficacy of doxorubicin by combining it with an HIF-1α inhibitor in a model of hepatocellular carcinoma. During this study, it was established that the most effective suppression of tumor growth occurred in group 3, in animals with reduced blood flow and the administration of doxorubicin, where the mean volume of tumor nodules was significantly smaller than the mean volume in the control group. In Group 2, in animals with reduced blood flow and the use of a combination of doxorubicin and bortezomib, the mean tumor node volume did not differ statistically from the volume of tumor nodes in the control group. Our findings indicate that a reduction in hepatic vascular blood flow in conjunction with doxorubicin exerts a pronounced inhibitory impact on the proliferation of intrahepatic tumor nodes. However, the introduction of bortezomib to this regimen does not result in the inhibition of tumor growth. Our results provide a rationale for a more comprehensive investigation of the mechanisms underlying the antitumor response or the reasons for its absence, as well as alternative candidates for HCC therapy.

1. Influence of hypoxia on the proliferative activity of cells of orthotopic xenophobicity hepatocellular carcinoma of liver in experiment / T.M. Kecheryukova [et al. ] // South Russian Cancer Journal. 2024. Vol. 5. No. 2. P. 35-42.

2. Metachronous primary multiple cancer of the head of the pancreas and liver: a case of development of hepatocellular carcinoma 10 years later after pancreatoduodenal resection / Kit O. I. et al. // Experimental and clinical gastroenterology. 2021. No. 11 (195). P. 79-83

3. Simulation of liver hypoxia in an experiment in vivo / A. S. Goncharov [et al.] // Yakut medical journal. 2023. No. 2.

4. Baiz D. et al. Bortezomib arrests the proliferation of hepatocellular carcinoma cells HepG2 and JHH6 by differentially affecting E2F1, p21 and p27 levels // Biochimie. 2009. Vol. 91. No. 3. P. 373-382

5. Ciombor K. K. et al. Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group // Investigational new drugs. 2014. Т. 32. P. 1017-1027.

6. Deng F. et al. Development and validation of a prognostic classifier based on HIF-1 signaling for hepatocellular carcinoma // Aging (Albany NY). 2020. Vol. 12. No. 4. P. 3431.

7. Farshbaf M. et al. Enhanced BBB and BBTB penetration and improved anti-glioma behavior of Bortezomib through dual-targeting nanostructured lipid carriers // Journal of Controlled Release. 2022. Vol. 345. P. 371-384

8. Farshbaf M. et al. Enhanced BBB and BBTB penetration and improved anti-glioma behavior of Bortezomib through dual-targeting nanostructured lipid carriers // Journal of Controlled Release. 2022. Vol. 345. P. 371-384

9. Lee Y. J. et al. A phase II trial to evaluate the efficacy of Bortezomib and liposomal doxorubicin in patients with BRCA Wild-type platinum-resistant recurrent ovarian cancer (KGOG 3044/EBLIN) // in vivo. 2022. Vol. 36. No. 4. P. 1949-1958.

10. Mitsiades N. et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications //Blood, The Journal of the American Society of Hematology. 2003. Vol. 101. No. 6. P. 2377-2380.

11. Petrillo M. et al. Hypoxia and tumor angiogenesis in the era of hepatocellular carcinoma transarterial loco-regional treatments // Future oncology. 2018. Vol. 14. No. 28. P. 2957-2967.

12. Sidali S. et al. New concepts in the treatment of hepatocellular carcinoma // United European gastroenterology journal. 2022. Vol. 10. No. 7. P. 765-774.

13. Sun X. et al. Visualizing the antivascular effect of bortezomib on the hypoxic tumor microenvironment // Oncotarget. 2015. Vol. 6. No. 33. P. 34732.

14. Wong C. C. L., Kai A. K. L., Ng I. O. L. The impact of hypoxia in hepatocellular carcinoma metastasis // Frontiers of medicine. 2014. Vol. 8. P. 33-41.