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A triple-drug combination induces apoptosis in cervical cancer-derived cell lines
Izamary Delgado-Waldo1,2, Carlos Contreras-Romero2,3, Sandra Salazar-Aguilar4
1Unidad de Bioquímica Guillermo Soberón Acevedo, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico.
Introduction:
Cervical cancer is a worldwide health problem due to the number of deaths caused by this neoplasm. In particular, in 2020, 30,000 deaths of this type of tumor were reported in Latin America. Treatments used to manage patients diagnosed in the early stages have excellent results as measured by different clinical outcomes. Existing first-line treatments are not enough to avoid cancer recurrence, progression, or metastasis in locally advanced and advanced stages. Therefore, there is a need to continue with the proposal of new therapies. Drug repositioning is a strategy to explore known medicines as treatments for other diseases. In this scenario, drugs used in other pathologies that have antitumor activity, such as metformin and sodium oxamate, are analyzed.
Methods:
In this research, we combined the drugs metformin and sodium oxamate with doxorubicin (named triple therapy or TT) based on their mechanism of action and previous investigation of our group against three CC cell lines.
Results:
Through flow cytometry, Western blot, and protein microarray experiments, we found TT-induced apoptosis on HeLa, CaSki, and SiHa through the caspase 3 intrinsic pathway, including the critical proapoptotic proteins BAD, BAX, cytochrome-C, and p21. In addition, mTOR and S6K phosphorylated proteins were inhibited in the three cell lines. Also, we show an anti-migratory activity of the TT, suggesting other targets of the drug combination in the late CC stages.
Discussion:
These results, together with our former studies, conclude that TT inhibits the mTOR pathway leading to cell death by apoptosis. Our work provides new evidence of TT against cervical cancer as a promising antineoplastic therapy.
Insights
Triple therapy combining metformin, sodium oxamate, and doxorubicin induces apoptosis and inhibits mTOR in cervical cancer cells. This drug repositioning strategy shows promise as a novel antineoplastic therapy for advanced cervical cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cervical cancer (CC) remains a significant global health issue, particularly in Latin America, with 30,000 deaths reported in 2020.
- Current first-line treatments are insufficient for locally advanced and advanced stages, often failing to prevent recurrence, progression, or metastasis.
- Drug repositioning offers a viable strategy to identify existing drugs with antitumor potential, such as metformin and sodium oxamate.
Purpose of the Study:
- To investigate the efficacy of a novel triple therapy (TT) combining metformin, sodium oxamate, and doxorubicin against cervical cancer.
- To elucidate the molecular mechanisms underlying the anti-cancer effects of this triple therapy.
- To evaluate the potential of TT as a new therapeutic approach for advanced cervical cancer.
Main Methods:
- Combination of metformin, sodium oxamate, and doxorubicin (TT) tested against three human cervical cancer cell lines (HeLa, CaSki, SiHa).
- Apoptosis induction assessed via flow cytometry and Western blot, analyzing key proteins in the intrinsic caspase 3 pathway (BAD, BAX, cytochrome-C, p21).
- Inhibition of the mTOR pathway (mTOR and S6K phosphorylation) and anti-migratory effects were evaluated.
Main Results:
- TT significantly induced apoptosis in all three cervical cancer cell lines through the intrinsic caspase 3 pathway.
- Key pro-apoptotic proteins (BAD, BAX, cytochrome-C, p21) were upregulated by TT.
- TT treatment led to the inhibition of mTOR and S6K phosphorylation and demonstrated anti-migratory activity.
Conclusions:
- The triple therapy (TT) effectively inhibits the mTOR pathway, inducing apoptosis and reducing migration in cervical cancer cells.
- This study provides compelling evidence for TT as a promising antineoplastic therapeutic strategy for cervical cancer.
- Drug repositioning of metformin and sodium oxamate in combination with doxorubicin offers a novel avenue for treating advanced cervical cancer.
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