Anticancer Activity of Sunitinib Analogues in Human Pancreatic Cancer Cell Cultures under Normoxia and Hypoxia
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Ieva Skaraitė1, Elias Maccioni2, Vilma Petrikaitė1
1Laboratory of Drug Targets Histopathology, Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50162 Kaunas, Lithuania.
Abstract:
Pancreatic cancer remains one of the deadliest cancer types. It is usually characterized by high resistance to chemotherapy. However, cancer-targeted drugs, such as sunitinib, recently have shown beneficial effects in pancreatic in vitro and in vivo models. Therefore, we chose to study a series of sunitinib derivatives developed by us, that were proven to be promising compounds for cancer treatment. The aim of our research was to evaluate the anticancer activity of sunitinib derivatives in human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 under normoxia and hypoxia. The effect on cell viability was determined by the MTT assay. The compound effect on cell colony formation and growth was established by clonogenic assay and the activity on cell migration was estimated using a 'wound healing' assay. Six out of 17 tested compounds at 1 µM after 72 h of incubation reduced cell viability by 90% and were more active than sunitinib. Compounds for more detailed experiments were chosen based on their activity and selectivity towards cancer cells compared to fibroblasts. The most promising compound EMAC4001 was 24 and 35 times more active than sunitinib against MIA PaCa-2 cells, and 36 to 47 times more active against the PANC-1 cell line in normoxia and hypoxia. It also inhibited MIA PaCa-2 and PANC-1 cell colony formation. Four tested compounds inhibited MIA PaCa-2 and PANC-1 cell migration under hypoxia, but none was more active than sunitinib. In conclusion, sunitinib derivatives possess anticancer activity in human pancreatic adenocarcinoma MIA PaCa-2 and PANC-1 cell lines, and they are promising for further research.
Insights
New sunitinib derivatives show significant anticancer activity against pancreatic cancer cell lines. These compounds are more effective than sunitinib, offering promising therapeutic potential for this deadly disease.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Pancreatic cancer is a highly lethal malignancy with significant resistance to conventional chemotherapy.
- Targeted therapies, including sunitinib, have demonstrated potential in preclinical pancreatic cancer models.
- Developing novel agents is crucial to overcome treatment resistance and improve patient outcomes.
Purpose of the Study:
- To evaluate the anticancer efficacy of novel sunitinib derivatives against human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1).
- To assess the activity of these derivatives under both normoxic and hypoxic conditions.
- To identify lead compounds with superior potency and selectivity compared to sunitinib.
Main Methods:
- Cell viability assessed using MTT assay.
- Colony formation evaluated via clonogenic assay.
- Cell migration studied using the 'wound healing' assay.
- Experiments conducted on MIA PaCa-2 and PANC-1 cell lines under normoxia and hypoxia.
Main Results:
- Six of 17 sunitinib derivatives exhibited >90% cell viability reduction at 1 µM after 72h, outperforming sunitinib.
- The lead compound EMAC4001 demonstrated significantly higher activity (24-47 times) than sunitinib against both cell lines.
- EMAC4001 effectively inhibited colony formation in MIA PaCa-2 and PANC-1 cells.
- Four compounds inhibited cell migration under hypoxia, though none surpassed sunitinib's efficacy.
Conclusions:
- Sunitinib derivatives possess potent anticancer activity against human pancreatic adenocarcinoma cell lines.
- The compound EMAC4001 is a highly promising candidate for further investigation in pancreatic cancer therapy.
- These novel derivatives warrant continued research for their therapeutic potential in pancreatic cancer treatment.
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