Abstract 592
Background
Metastatic colon cancer has a survival rate less than %5 despite the use of effective chemotherapeutic regimen. Prognostic and predictive importance of EGFR is still contradictive in colon cancer. Tyrosine kinase inhibitor canertinib was used in this study to block the EGFR receptor. The effect of Palladium (Pd) (II) compound [PdCl(terpy)](sac).2H2O] and canertinib combination treatment was investigated in this study. 5-fluorouracil (5-FU), a chemotherapeutic drug was used as positive control.
Methods
The cytotoxic effects of the combination of Pd (II)+canertinib and the 5-FU+canertinib combination on colon cancer cell line (HCT-15, HT-29) were determined by the SRB test. Apoptosis, the acidic vesiculations, mitochondrial depolarization were determined by flow cytometry, Annexin-V-Cy3/SYTOX, acridine orange, JC-1 staining. Alterations in proteins related to EGFR-associated pathway, EMT, apoptosis/autophagy and drug carrier were evaluated by western blot. Invasion, wound healing and colony forming ability were determined. Tube forming in HUVEC and vessel forming ability was assessed by matrigel and CAM test respectively.
Results
A significant decrease in p-ERK, p-P38, p-EGFR protein levels was observed with EGFR inhibition, while the cell viability was decreased. Cell death was determined as mitochondrial apoptosis. LC3-II, Beclin-1, Atg5 protein levels, and increased acidic vesicles and decreased p-MTOR protein levels were associated with increased autophagy in combination therapy. In addition, increased E-cadherin expression and decreased N-cadherin, fibronectin and vimentin expression related to decrease in invasion, migration, and colony forming ability. ROS expression and DNA damage increased. Significant differences in MDR-1 and MRP-1 protein levels were observed with EGFR inhibition. In addition, the ability to create tubes and vessels has decreased significantly.
Conclusions
EGFR inhibition along with Pd(II) has been shown to increased cytotoxicity, decreased invasion, migration and vessel formation abilities. Furthermore, induced ROS levels and increased autophagic signaling are found to be necessary for mitochondria-dependent apoptosis in colon cancer cells.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Uludag University.
Funding
Scientific Research Projects Foundation (BAP) of Uludag University of Turkey [Project No. (DDP(F)-2017)].
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2273 - High performance of serial tumor biopsies in first in human (FIH) phase I trials.
Presenter: Jun Sato
Session: Poster Display session 1
Resources:
Abstract
5933 - Response rates and lesion-level progression patterns of solid tumor patients in an academic phase 1 program: implications for tumor heterogeneity
Presenter: Christopher Chen
Session: Poster Display session 1
Resources:
Abstract
3569 - Clinical Benefit and Response Rate in Early Phase Clinical Trials: First Report from a Single-Institution Study
Presenter: Antonio Marra
Session: Poster Display session 1
Resources:
Abstract
4139 - Patient (pt) selection for immunotherapeutic early-phase clinical trials (ieCTs): a single Phase I Unit experience
Presenter: Matteo Simonelli
Session: Poster Display session 1
Resources:
Abstract
4451 - Improving patient selection for immuno-oncology phase 1 trials: an external validation of five prognostic scores at Claudius Regaud Institute of Toulouse, Oncopôle (IUCT-O).
Presenter: Ghassan Al Darazi
Session: Poster Display session 1
Resources:
Abstract
1696 - Demonstrating the Changing Trends in Phase 1 Clinical Trials
Presenter: Christina Guo
Session: Poster Display session 1
Resources:
Abstract
3202 - Participation of Women in phase 1 oncology clinical trials
Presenter: Laura Vidal
Session: Poster Display session 1
Resources:
Abstract
4518 - Predictors for early trial discontinuation of patients with cancer participating in phase I clinical trials
Presenter: Joeri Douma
Session: Poster Display session 1
Resources:
Abstract
4368 - Safety of Tumor Treating Fields delivery to the torso: Meta analysis from TTFields clinical trials
Presenter: Federica Grosso
Session: Poster Display session 1
Resources:
Abstract
4615 - Proteomic Profiling Identifies Molecular Basis of Adverse Event to BPM31510 Exposure: Rationale for Comprehensive Molecular Pharmacodynamics (PD) in Phase 1 Clinical Trial Design
Presenter: Vivek Subbiah
Session: Poster Display session 1
Resources:
Abstract