Article ; Online: The potential effect of Schisandrin-B combination with panitumumab in wild-type and mutant colorectal cancer cell lines: Role of apoptosis and autophagy.
Journal of biochemical and molecular toxicology
2023 Volume 37, Issue 5, Page(s) e23324
Abstract: Panitumumab is an approved monoclonal antibody for the treatment of colorectal cancer (CRC); however, mutations in EGFR signaling pathway resulted in poor response. Schisandrin-B (Sch-B) is a phytochemical that was suggested to protect against ... ...
| Abstract | Panitumumab is an approved monoclonal antibody for the treatment of colorectal cancer (CRC); however, mutations in EGFR signaling pathway resulted in poor response. Schisandrin-B (Sch-B) is a phytochemical that was suggested to protect against inflammation, oxidative stress, and cell proliferation. The present study aimed to investigate the potential effect of Sch-B on panitumumab-induced cytotoxicity in wild-type Caco-2, and mutant HCT-116 and HT-29 CRC cell lines, and the possible underlying mechanisms. CRC cell lines were treated with panitumumab, Sch-B, and their combination. The cytotoxic effect of drugs was determined by MTT assay. The apoptotic potential was assessed in-vitro by DNA fragmentation and caspase-3 activity. Additionally, autophagy was investigated via microscopic detection of autophagosomes and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) measurement of Beclin-1, Rubicon, LC3-II, and Bcl-2 expression. The drug pair enhanced panitumumab cytotoxicity in all CRC cell lines where IC50 of panitumumab was decreased in Caco-2 cell line. Apoptosis was induced through caspase-3 activation, DNA fragmentation, and Bcl-2 downregulation. Caco-2 cell line treated with panitumumab showed stained acidic vesicular organelles, contrariwise, all cell lines treated with Sch-B or the drug pair displayed green fluorescence indicating the lack of autophagosomes. qRT-PCR revealed the downregulation of LC3-II in all CRC cell lines, Rubicon in mutant cell lines, and Beclin-1 in HT-29 cell line only. Sch-B at 6.5 µM promoted panitumumab-induced apoptotic cell death, in-vitro, via caspase-3 activation and Bcl-2 downregulation, rather than autophagic cell death. This novel combination therapy against CRC, allows the reduction of panitumumab dose to guard against its adverse effects. |
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| MeSH term(s) | Humans ; Panitumumab/pharmacology ; Panitumumab/therapeutic use ; Caco-2 Cells ; Beclin-1/metabolism ; Caspase 3 ; Apoptosis ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Autophagy ; Proto-Oncogene Proteins c-bcl-2 |
| Chemical Substances | Panitumumab (6A901E312A) ; schizandrin (G01BQC0879) ; Beclin-1 ; Caspase 3 (EC 3.4.22.-) ; Proto-Oncogene Proteins c-bcl-2 |
| Language | English |
| Publishing date | 2023-02-19 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 1410020-4 |
| ISSN | 1099-0461 ; 1095-6670 |
| ISSN (online) | 1099-0461 |
| ISSN | 1095-6670 |
| DOI | 10.1002/jbt.23324 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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