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Recent Scientific Developments in Metastatic Prostate Cancer
Open AccessArticle

Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis

1
Department of Urology and Pediatric Urology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
2
Institute of Medical Virology, Goethe-University, 60596 Frankfurt, Germany
3
Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK
4
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Isabel Heidegger-Pircher
Cancers 2021, 13(4), 882; https://doi.org/10.3390/cancers13040882
Received: 18 December 2020 / Revised: 12 February 2021 / Accepted: 15 February 2021 / Published: 20 February 2021
(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)
Prostate carcinoma (PCa) is the most common tumor in men with an increasing age-associated risk. Several therapy strategies, one of which is docetaxel (DX) chemotherapy, have been established. However, due to the development of therapy resistance, in which chemotherapy no longer effectively combats the cancer, advanced, metastasized PCa with a poor prognosis may become manifested and therapy inevitably fails. Thus, new treatment options are urgently needed. Shikonin (SHI), from Traditional Chinese Medicine, has revealed promising antitumor activity in several tumor entities. In the current study, the impact of SHI on four therapy-sensitive and four respective DX-resistant PCa cell lines was determined. SHI induced growth inhibition mainly by necroptosis, a type of cell death, in all the tested therapy-sensitive, but more importantly, DX-resistant PCa cell lines. Corresponding molecular alterations contributing to growth inhibition after SHI exposure were found. SHI could, therefore, be a promising additive in treating advanced PCa.
The prognosis for advanced prostate carcinoma (PCa) remains poor due to development of therapy resistance, and new treatment options are needed. Shikonin (SHI) from Traditional Chinese Medicine has induced antitumor effects in diverse tumor entities, but data related to PCa are scarce. Therefore, the parental (=sensitive) and docetaxel (DX)-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1–1.5 μM], and tumor cell growth, proliferation, cell cycling, cell death (apoptosis, necrosis, and necroptosis), and metabolic activity were evaluated. Correspondingly, the expression of regulating proteins was assessed. Exposure to SHI time- and dose-dependently inhibited tumor cell growth and proliferation in parental and DX-resistant PCa cells, accompanied by cell cycle arrest in the G2/M or S phase and modulation of cell cycle regulating proteins. SHI induced apoptosis and more dominantly necroptosis in both parental and DX-resistant PCa cells. This was shown by enhanced pRIP1 and pRIP3 expression and returned growth if applying the necroptosis inhibitor necrostatin-1. No SHI-induced alteration in metabolic activity of the PCa cells was detected. The significant antitumor effects induced by SHI to parental and DX-resistant PCa cells make the addition of SHI to standard therapy a promising treatment strategy for patients with advanced PCa. View Full-Text
Keywords: prostate cancer (PCa); docetaxel (DX) resistance; shikonin (SHI); Traditional Chinese Medicine (TCM); growth inhibition; apoptosis; necroptosis prostate cancer (PCa); docetaxel (DX) resistance; shikonin (SHI); Traditional Chinese Medicine (TCM); growth inhibition; apoptosis; necroptosis
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MDPI and ACS Style

Markowitsch, S.D.; Juetter, K.M.; Schupp, P.; Hauschulte, K.; Vakhrusheva, O.; Slade, K.S.; Thomas, A.; Tsaur, I.; Cinatl, J., Jr.; Michaelis, M.; Efferth, T.; Haferkamp, A.; Juengel, E. Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis. Cancers 2021, 13, 882. https://doi.org/10.3390/cancers13040882

AMA Style

Markowitsch SD, Juetter KM, Schupp P, Hauschulte K, Vakhrusheva O, Slade KS, Thomas A, Tsaur I, Cinatl J Jr., Michaelis M, Efferth T, Haferkamp A, Juengel E. Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis. Cancers. 2021; 13(4):882. https://doi.org/10.3390/cancers13040882

Chicago/Turabian Style

Markowitsch, Sascha D.; Juetter, Kira M.; Schupp, Patricia; Hauschulte, Kristine; Vakhrusheva, Olesya; Slade, Kimberly S.; Thomas, Anita; Tsaur, Igor; Cinatl, Jindrich, Jr.; Michaelis, Martin; Efferth, Thomas; Haferkamp, Axel; Juengel, Eva. 2021. "Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis" Cancers 13, no. 4: 882. https://doi.org/10.3390/cancers13040882

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