TY  - JOUR
A1  - Markowitsch, Sascha D.
A1  - Juetter, Kira M.
A1  - Schupp, Patricia
A1  - Hauschulte, Kristine
A1  - Vakhrusheva, Olesya
A1  - Slade, Kimberly Sue
A1  - Thomas, Anita
A1  - Tsaur, Igor
A1  - Cinatl, Jindrich
A1  - Michaelis, Martin
A1  - Efferth, Thomas
A1  - Haferkamp, Axel
A1  - Jüngel, Eva
T1  - Shikonin reduces growth of docetaxel-resistant prostate cancer cells mainly through necroptosis
T2  - Cancers
N2  - Simple Summary: 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.
Abstract: 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.
KW  - prostate cancer (PCa)
KW  - docetaxel (DX) resistance
KW  - shikonin (SHI)
KW  - Traditional Chinese Medicine (TCM)
KW  - growth inhibition
KW  - apoptosis
KW  - necroptosis
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62152
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-621526
SN  - 2072-6694
N1  - This research was funded by the Friedrich-Spicker-Stiftung (E.J.), grant number 01-2017; Hilfe für krebskranke Kinder Frankfurt e.V. (J.C. Jr.), Frankfurter Stiftung für krebskranke Kinder (J.C. Jr.), Kent Cancer Trust (M.M.).
VL  - 13
IS  - 4, art. 882
SP  - 1
EP  - 23
PB  - MDPI
CY  - Basel
ER  -