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The Synergistic Anti-colon Cancer Effect of Aurora A Inhibitors and AKT Inhibitors Through PI3K/AKT Pathway
Cheng Sun1, Zhen Qu2, Weilin Liu3
1Medical Oncology Division, Qingdao Chengyang People's Hospital, Qingdao 266109, Shandong Province, China
Background:
Both AKT and Aurora inhibitors are a potential therapeutic agent for the treatment of malignant tumors. However, the role of combined inhibition of AKT and Aurora in colon cancer and its underlying mechanism have yet to be fully investigated.
Objective:
To investigate the role of combined AKT and Aurora inhibitors in colon cancer and its underlying mechanisms.
Methods:
CCK8 assay, colony formation assay, and flow cytometry were performed to analyze the proliferation and apoptosis of colon cancer cell line SW480 treated with combined AKT inhibitor MK2206 and Aurora inhibitor Alisertib, respectively. And tumor formation and growth were measured in tumor allograft model mice administered with the combined inhibitors. Western blot analysis was used to examine the expression levels of apoptosis-related proteins and signal transduction pathway components. The PI3K agonist 740Y-P and Overexpression of AKT are used to verify whether the PI3K/AKT pathway plays an anti-tumor effect when combined with inhibitory administration.
Results:
Aurora A inhibitor Alisertib and AKT inhibitor MK2206 displayed consistent and synergistic antiproliferation and proapoptotic effects. Combined inhibition of Aurora A and AKT down-regulated the expression of Bcl-2/Bax and up-regulated the expression of cleaved-caspase-3 and cleaved-PARP. While single-drug treatment can significantly inhibit the expression of P-PI3K and P-AKT as well as increase the expression of P53 and H2A.X, the combined drugs had a more significant inhibitory effect than the single drug. Moreover, administration of PI3K agonist 740Y-P and AKT1 overexpression in experiments proved that the combined drugs exert an anticancer effect by inhibiting the PI3K/AKT pathway. Meanwhile, we showed that the combined administration had an anti-colon cancer effect on tumor allograft mice, and the underlying mechanism involved inhibition of the PI3K/AKT pathway.
Conclusion:
Combined administration of Aurora A inhibitor Alisertib and AKT inhibitor MK2206 can inhibit the proliferation of colon cancer cells and induce apoptosis, while inhibiting tumor growth in vivo. The underlying mechanism may involve the PI3K/AKT pathway and DNA damage pathway.
Insights
Combined AKT and Aurora inhibitors synergistically reduce colon cancer cell proliferation and induce apoptosis. This combination therapy effectively inhibits tumor growth in vivo, primarily through the PI3K/AKT pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- AKT and Aurora inhibitors show promise as anti-cancer agents.
- The combined effect and mechanism of AKT and Aurora inhibition in colon cancer remain under-investigated.
Purpose of the Study:
- To investigate the synergistic effects of combined AKT and Aurora inhibitors on colon cancer.
- To elucidate the underlying molecular mechanisms of this combined inhibition.
Main Methods:
- Utilized CCK8, colony formation assays, and flow cytometry to assess proliferation and apoptosis in SW480 colon cancer cells treated with MK2206 (AKT inhibitor) and Alisertib (Aurora inhibitor).
- Evaluated tumor formation and growth in a mouse allograft model. Western blot analysis examined apoptosis-related proteins and signaling pathways.
- Investigated the role of the PI3K/AKT pathway using a PI3K agonist and AKT overexpression.
Main Results:
- Combined MK2206 and Alisertib demonstrated synergistic anti-proliferation and pro-apoptotic effects.
- The combination therapy downregulated Bcl-2/Bax and upregulated cleaved-caspase-3/PARP, indicating enhanced apoptosis.
- Combined inhibition significantly suppressed P-PI3K, P-AKT, and upregulated P53/H2A.X, with greater efficacy than single agents. In vivo studies confirmed anti-colon cancer effects via PI3K/AKT pathway inhibition.
Conclusions:
- Combined administration of Aurora A inhibitor Alisertib and AKT inhibitor MK2206 inhibits colon cancer cell proliferation and induces apoptosis.
- This combination therapy suppresses tumor growth in vivo, potentially through mechanisms involving the PI3K/AKT and DNA damage pathways.
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