Efficacy of metformin in mediating cellular uptake and inducing apoptosis activity of doxorubicin

Shafa, Maryam Hosseini; Jalal, Razieh; Kosari, Negin; Rahmani, Farzad

doi:10.1016/j.yrtph.2018.09.023

Cited by 15 publications

(14 citation statements)

References 53 publications

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“…We also found a higher incidence of death among rats receiving both DOX and MET [30]. Therefore, co-administration of MET with DOX may increase drug toxicity or produce a synergistic effect against all cells leading to death.…”

Section: Discussionmentioning

confidence: 51%

Effect of Metformin on Doxorubicin-Induced Memory Dysfunction

Alharbi

Almogbel

et al. 2020

Brain Sciences

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Doxorubicin (DOX) is widely used to treat many types of cancer; however, it is associated with chemotherapy-related complications such as cognitive dysfunction, known as chemobrain. Chemobrain affects up to 75% of cancer survivors, and there are currently no available therapeutic options. This study aims to examine whether metformin (MET) can protect against the neurotoxicity caused by DOX treatment. Forty male rats were divided into four groups (10 rats/group): control, DOX, DOX + MET, and MET. Rats treated with DOX received five doses of 4 mg/kg DOX weekly (cumulative dose: 20 mg/kg). For the DOX-MET and MET groups, MET (3 mg/mL) was dissolved in drinking water. Behavioral and glucose tests were performed one day after treatment was completed. We found DOX (4 mg/kg/week, 5 weeks) caused learning and memory impairment in the Y-maze, novel object recognition, and elevated plus maze behavioral tests. MET did not rescue these DOX-induced memory impairments. Neither DOX nor MET nor MET + DOX altered glucose levels following the treatment. In summary, DOX treatment is associated with memory impairment in rats, but MET does not rescue this cognitive dysfunction.

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Section: Discussionmentioning

confidence: 51%

Effect of Metformin on Doxorubicin-Induced Memory Dysfunction

Alharbi

Almogbel

et al. 2020

Brain Sciences

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“…In various in vitro and in vivo studies metformin was shown to decrease Dox-induced cardiotoxicity and is considered as a promising approach for patients treating with Dox [ 19 ]. Moreover, metformin could not only reduce the therapeutic concentration of Dox and diminish cardiotoxic side effects, but also shows synergistic anti-tumor effects for prostate [ 42 ] and breast cancer [ 19 , 43 – 47 ] in different cell and mouse models. However, in the present study metformin could not improve the anticancer effects of Dox in the BALB-TTM.…”

Section: Discussionmentioning

confidence: 99%

Metformin alters therapeutic effects in the BALB/c tumor therapy model

et al. 2021

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Background Despite considerable medical proceedings, cancer is still a leading cause of death. Major problems for tumor therapy are chemoresistance as well as toxic side effects. In recent years, the additional treatment with the antidiabetic drug metformin during chemotherapy showed promising results in some cases. The aim of this study was to develop an in vitro tumor therapy model in order to further investigate the potential of a combined chemotherapy with metformin. Methods Cytotoxic effects of a combined treatment on BALB/c fibroblasts were proven by the resazurin assay. Based on the BALB/c cell transformation assay, the BALB/c tumor therapy model was established successfully with four different and widely used chemotherapeutics from different categories. Namely, Doxorubicin as a type-II isomerase inhibitor, Docetaxel as a spindle toxin, Mitomycin C as an alkylating agent and 5-Fluorouracil as an antimetabolite. Moreover, glucose consumption in the medium supernatant was measured and protein expressions were determined by Western Blotting. Results Initial tests for the combined treatment with metformin indicated unexpected results as metformin could partly mitigate the cytotoxic effects of the chemotherapeutic agents. These results were further confirmed as metformin induced resistance to some of the drugs when applied simultaneously in the tumor therapy model. Mechanistically, an increased glucose consumption was observed in non-transformed cells as well as in the mixed population of malignant transformed cell foci and non-transformed monolayer cells, suggesting that metformin could also increase glucose consumption in transformed cells. Conclusion In conclusion, this study suggests a cautious use of metformin during chemotherapy. Moreover, the BALB/c tumor therapy model offers a potent tool for further mechanistic studies of drug-drug interactions during cancer therapy. Graphical abstract

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“…However, the mechanism of such potentiating action of bioenergetic inhibitors and their action on cancer cells with different resistant phenotypes is still known not completely [ 20 , 23 , 30 , 31 , 32 , 33 ]. Only single observations demonstrate the possible targets of bioenergetic inhibitors—from the suppression of ABC transporters to activation of AMPK signaling [ 34 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…[ 15 , 37 ]. Several studies demonstrate the additional inhibition of tumor growth under the combination of metformin with various cytostatic drugs [ 15 , 36 , 38 ]; however, the mechanism of such cooperative effects still not clear.…”

Section: Discussionmentioning

confidence: 99%

Metformin Restores the Drug Sensitivity of MCF-7 Cells Resistant Derivates via the Cooperative Modulation of Growth and Apoptotic-Related Pathways

et al. 2020

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The phenomenon of the primary or acquired resistance of cancer cells to antitumor drugs is among the key problems of oncology. For breast cancer, the phenomenon of the resistance to hormonal or target therapy may be based on the numerous mechanisms including the loss or mutation of estrogen receptor, alterations of antiapoptotic pathways, overexpression of growth-related signaling proteins, etc. The perspective approaches for overcoming the resistance may be based on the usage of compounds such as inhibitors of the cell energetic metabolism. Among the latter, the antidiabetic drug metformin exerts antitumor activity via the activation of AMPK and the subsequent inhibition of mTOR signaling. The experiments were performed on the ERα-positive MCF-7 breast cancer cells, the MCF-7 sublines resistant to tamoxifen (MCF-7/T) and rapamycin (MCF-7/Rap), and on triple-negative MDA-MB-231 breast cancer cells. We have demonstrated metformin’s ability to enhance the cytostatic activity of the tamoxifen and rapamycin on both parent MCF-7 cells and MCF-7-resistant derivates mediated via the suppression of mTOR signaling and growth-related transcriptional factors. The cooperative effect of metformin and tested drugs was realized in an estrogen-independent manner, and, in the case of tamoxifen, was associated with the activation of apoptotic cell death. Similarly, the stimulation of apoptosis under metformin/tamoxifen co-treatment was shown to occur in the MCF-7 cells after steroid depletion as well as in the ERα-negative MDA-MB-231 cells. We conclude that metformin co-treatment may be used for the increase and partial restoration of the cancer cell sensitivity to hormonal and target drugs. Moreover, the combination of metformin with tamoxifen induces the apoptotic death in the ERα-negative breast cancer cells opening the additional perspectives in the treatment of estrogen-independent breast tumors.

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Efficacy of metformin in mediating cellular uptake and inducing apoptosis activity of doxorubicin

Cited by 15 publications

References 53 publications

Effect of Metformin on Doxorubicin-Induced Memory Dysfunction

Effect of Metformin on Doxorubicin-Induced Memory Dysfunction

Metformin alters therapeutic effects in the BALB/c tumor therapy model

Metformin Restores the Drug Sensitivity of MCF-7 Cells Resistant Derivates via the Cooperative Modulation of Growth and Apoptotic-Related Pathways

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