Complementary Targeting of Rb Phosphorylation and Growth in Cervical Cancer Cell Cultures and a Xenograft Mouse Model by SHetA2 and Palbociclib
| Autor: | Stanley Lightfoot, Amy L. Kennedy, Zitha Redempta Isingizwe, Rajani Rai, Doris M. Benbrook, Yan D. Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research SHetA2 cervical cancer cyclin D1 Palbociclib lcsh:RC254-282 Article retinoblastoma 03 medical and health sciences 0302 clinical medicine Cyclin D1 Cyclin-dependent kinase medicine Cervical cancer biology Chemistry Retinoblastoma palbociblib medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Blot 030104 developmental biology Oncology Cell culture Apoptosis 030220 oncology & carcinogenesis biology.protein Cancer research |
| Zdroj: | Cancers, Vol 12, Iss 1269, p 1269 (2020) Cancers Volume 12 Issue 5 |
| ISSN: | 2072-6694 |
| Popis: | Cervical cancer is caused by high-risk human papillomavirus (HPV) types and treated with conventional chemotherapy with surgery and/or radiation. HPV E6 and E7 proteins increase phosphorylation of retinoblastoma (Rb) by cyclin D1/cyclin dependent kinase (CDK)4/6 complexes. We hypothesized that cyclin D1 degradation by the SHetA2 drug in combination with palbociclib inhibition of CDK4/6 activity synergistically reduces phosphorylated Rb (phospho-Rb) and inhibits cervical cancer growth. The effects of these drugs, alone, and in combination, were evaluated in SiHa and CaSki HPV-positive and C33A HPV-negative cervical cancer cell lines using cell culture, western blots and ELISA, and in a SiHa xenograft model. Endpoints were compared by isobolograms, ANOVA, and Chi-Square. In all cell lines, combination indexes documented synergistic interaction of SHetA2 and palbociclib in association SHetA2 reduction of cyclin D1 and phospho-Rb, palbociclib reduction of phospho-Rb, and enhanced phospho-Rb reduction upon drug combination. Both drugs significantly reduced phospho-Rb and growth of SiHa xenograft tumors as single agents and acted additively when combined, with no evidence of toxicity. Dilated CD31-negative blood vessels adjacent to, or within, areas of necrosis and apoptosis were observed in all drug-treated tumors. These results justify development of the SHetA2 and palbociclib combination for targeting phospho-Rb in cervical cancer treatment. |
| Databáze: | OpenAIRE |
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