Complementary Targeting of Rb Phosphorylation and Growth in Cervical Cancer Cell Cultures and a Xenograft Mouse Model by SHetA2 and Palbociclib

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 cycli...

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Bibliographic Details
Published in:Cancers 2020-05, Vol.12 (5), p.1269
Main Authors: Kennedy, Amy L, Rai, Rajani, Isingizwe, Zitha Redempta, Zhao, Yan Daniel, Lightfoot, Stanley A, Benbrook, Doris M
Format: Article
Language:English
Subjects:
Apoptosis
Blood vessels
Cancer
Cancer therapies
Cell culture
Cell cycle
Cervical cancer
Cervix
Chemotherapy
Cyclin D1
Cyclin-dependent kinase 4
Drug dosages
Human papillomavirus
Kinases
Mutation
Phosphorylation
Proteins
Retina
Retinoblastoma
Surgery
Toxicity
Tumor cell lines
Tumors
Western blotting
Xenografts
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12051269