Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer
Endometrial cancer patients with advanced disease or high recurrence risk are treated with chemotherapy. Our objective was to evaluate the utility and mechanism of a novel drug, SHetA2, alone and in combination with paclitaxel, in endometrial cancer. SHetA2 targets the HSPA chaperone proteins, Grp78...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/10/2322 |
| _version_ | 1797534402781118464 |
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| author | Vishal Chandra Rajani Rai Doris Mangiaracina Benbrook |
| author_facet | Vishal Chandra Rajani Rai Doris Mangiaracina Benbrook |
| author_sort | Vishal Chandra |
| collection | DOAJ |
| description | Endometrial cancer patients with advanced disease or high recurrence risk are treated with chemotherapy. Our objective was to evaluate the utility and mechanism of a novel drug, SHetA2, alone and in combination with paclitaxel, in endometrial cancer. SHetA2 targets the HSPA chaperone proteins, Grp78, hsc70, and mortalin, which have high mutation rates in endometrial cancer. SHetA2 effects on cancerous phenotypes, mitochondria, metabolism, protein expression, mortalin/client protein complexes, and cell death were evaluated in AN3CA, Hec13b, and Ishikawa endometrial cancer cell lines, and on growth of Ishikawa xenografts. In all three cell lines, SHetA2 inhibited anchorage-independent growth, migration, invasion, and ATP production, and induced G1 cell cycle arrest, mitochondrial damage, and caspase- and apoptosis inducing factor (AIF)-mediated apoptosis. These effects were associated with altered levels of proteins involved in cell cycle regulation, mitochondrial function, protein synthesis, endoplasmic reticulum stress, and metabolism; disruption of mortalin complexes with mitochondrial and metabolism proteins; and inhibition of oxidative phosphorylation and glycolysis. SHetA2 and paclitaxel exhibited synergistic combination indices in all cell lines and exerted greater xenograft tumor growth inhibition than either drug alone. SHetA2 is active against endometrial cancer cell lines in culture and in vivo and acts synergistically with paclitaxel. |
| first_indexed | 2024-03-10T11:30:06Z |
| format | Article |
| id | doaj.art-cd1a20b6335941fb8a7be9fc94cebbae |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:30:06Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-cd1a20b6335941fb8a7be9fc94cebbae2023-11-21T19:22:15ZengMDPI AGCancers2072-66942021-05-011310232210.3390/cancers13102322Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial CancerVishal Chandra0Rajani Rai1Doris Mangiaracina Benbrook2Gynecologic Oncology Section, Stephenson Cancer Center, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USAGynecologic Oncology Section, Stephenson Cancer Center, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USAGynecologic Oncology Section, Stephenson Cancer Center, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USAEndometrial cancer patients with advanced disease or high recurrence risk are treated with chemotherapy. Our objective was to evaluate the utility and mechanism of a novel drug, SHetA2, alone and in combination with paclitaxel, in endometrial cancer. SHetA2 targets the HSPA chaperone proteins, Grp78, hsc70, and mortalin, which have high mutation rates in endometrial cancer. SHetA2 effects on cancerous phenotypes, mitochondria, metabolism, protein expression, mortalin/client protein complexes, and cell death were evaluated in AN3CA, Hec13b, and Ishikawa endometrial cancer cell lines, and on growth of Ishikawa xenografts. In all three cell lines, SHetA2 inhibited anchorage-independent growth, migration, invasion, and ATP production, and induced G1 cell cycle arrest, mitochondrial damage, and caspase- and apoptosis inducing factor (AIF)-mediated apoptosis. These effects were associated with altered levels of proteins involved in cell cycle regulation, mitochondrial function, protein synthesis, endoplasmic reticulum stress, and metabolism; disruption of mortalin complexes with mitochondrial and metabolism proteins; and inhibition of oxidative phosphorylation and glycolysis. SHetA2 and paclitaxel exhibited synergistic combination indices in all cell lines and exerted greater xenograft tumor growth inhibition than either drug alone. SHetA2 is active against endometrial cancer cell lines in culture and in vivo and acts synergistically with paclitaxel.https://www.mdpi.com/2072-6694/13/10/2322endometrial cancerSHetA2paclitaxelcell cycle arrestmitochondriametabolism |
| spellingShingle | Vishal Chandra Rajani Rai Doris Mangiaracina Benbrook Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer Cancers endometrial cancer SHetA2 paclitaxel cell cycle arrest mitochondria metabolism |
| title | Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer |
| title_full | Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer |
| title_fullStr | Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer |
| title_full_unstemmed | Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer |
| title_short | Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer |
| title_sort | utility and mechanism of sheta2 and paclitaxel for treatment of endometrial cancer |
| topic | endometrial cancer SHetA2 paclitaxel cell cycle arrest mitochondria metabolism |
| url | https://www.mdpi.com/2072-6694/13/10/2322 |
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