Cell-cycle dependent antagonistic interactions between paclitaxel and carboplatin in combination therapy

Xiong, Xiaoxiong; Sui, Meihua; Fan, Weimin; Kraft, Andrew S.

doi:10.4161/cbt.6.7.4323

Cited by 27 publications

(23 citation statements)

References 22 publications

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“…In contrast to the cooperative effect of emtricitabine/tenofovir with doxorubicin, emtricitabine/tenofovir revealed an inhibitory effect on the efficacy of taxol. Similar antagonistic effects of taxol have previously been described [15][16][17], indicating that the main effect of taxol, mitotic spindle inhibition in the G2/M phase, is impeded by drugs that interfere with cell cycle progression at earlier stages [17]. Cell cycle arrest by DNA-damaging agents, either by nucleotide antagonists, intercalating agents, alkylating drugs, or radiation, is well known to induce a transient cell cycle arrest for DNA repair processes before DNA replication resumes [18,19].…”

Section: Discussionmentioning

confidence: 82%

The HIV reverse transcriptase inhibitor tenofovir induces cell cycle arrest in human cancer cells

et al. 2011

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Selected HIV drugs, either of the protease inhibitor type or the nucleoside antagonist type, have been shown to exert tumoricidal effects. Here, we show that the HIV reverse transcriptase inhibitor Truvada, a combination drug of the cytidine analogue emtricitabine and the adenosine analogue tenofovir, induces DNA damage and cell cycle arrest in human cancer cells. Phosphorylation of the DNA repair enzyme H2AX by emtricitabine/tenofovir indicated that it interfered with the integrity of the DNA and replication machinery in human cancer cells. Long term incubation of cancer cells with emtricitabine/tenofovir caused the formation of multi-nuclear giant cells, further indicating DNA replication problems. When tested as single agents, the anti-tumoral activity of emtricitabine/tenofovir was predominantly caused by tenofovir, although the combination with emtricitabine enhanced its effect on cancer cells. Combined with established anti-cancer drugs, emtricitabine/tenofovir was preferentially found to enhance the cytotoxic effect of doxorubicin, a promising drug for the treatment of relapsed, chemoresistant cancer. These results show that especially the adenosine analogue tenofovir could be used to interfere with the proliferation machinery of human cancer cells and to be applied for chemosensitization of cancer cells to already established DNA-interacting drugs.

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Section: Discussionmentioning

confidence: 82%

The HIV reverse transcriptase inhibitor tenofovir induces cell cycle arrest in human cancer cells

et al. 2011

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“…Cell cycle arrest is an important step of cytostasis. Paclitaxel and vincristine cause mainly G2/M phase arrest, but carboplatin and cytarabine stop the cell cycle in S phase, usually [4,19,20,31].…”

Section: Discussionmentioning

confidence: 99%

In vitro effect of carboplatin, cytarabine, paclitaxel, vincristine, and low‐power laser irradiation on murine mesenchymal stem cells

et al. 2009

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“…By changing the scheduling of paclitaxel and carboplatin in combination therapy, it has been observed that carboplatin inhibited paclitaxel-induced IkBa degradation and bcl-2 phosphorylation and thus antagonized the cytotoxic effects of the latter drug. 29 The authors of this article concluded that for optimal interaction between paclitaxel and carboplatin, the schedule of addition is crucial. Herein, we also postulate that optimal scheduling of metformin and chemotherapy is required to obtain beneficial results.…”

Section: Discussionmentioning

confidence: 99%

“…29 To this end, we studied different combinations of metformin in addition to obtaining an initial idea on the interaction between metformin and the 3 cytotoxic chemotherapies tested. We observed that pretreatment of metformin for 24 hours or the combination of metformin with paclitaxel for 48 hours interfered with the cytotoxic effects of paclitaxel in both the cell lines.…”

Section: Discussionmentioning

confidence: 99%

Metformin, at Concentrations Corresponding to the Treatment of Diabetes, Potentiates the Cytotoxic Effects of Carboplatin in Cultures of Ovarian Cancer Cells

et al. 2013

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The use of the type 2 diabetics drug metformin has been correlated with enhanced progression-free survival in ovarian cancer. The literature has speculated that this enhancement is due to the high concentration of metformin directly causing cancer cell death. However, this explanation does not fit with clinical data reporting that the women exposed to constant micromolar concentrations of metformin, as present in the treatment of diabetes, respond better to chemotherapy. Herein, our aim was to examine whether micromolar concentrations of metformin alone could bring about cancer cell death and whether micromolar metformin could increase the cytotoxic effect of commonly used chemotherapies in A2780 and SKOV3 cell lines and primary cultured cancer cells isolated from the peritoneal fluid of patients with advanced ovarian cancer. Our results in cell lines demonstrate that no significant loss of viability or change in cell cycle was observed with micromolar metformin alone; however, we observed cytotoxicity with micromolar metformin in combination with chemotherapy at concentrations where the chemotherapy alone produced no loss in viability. We demonstrate that previous exposure and maintenance of metformin in conjunction with carboplatin produces a synergistic enhancement in cytotoxicity of A2780 and SKOV3 cells (55% and 43%, respectively). Furthermore, in 5 (44%) of the 11 ovarian cancer primary cultures, micromolar metformin improved the cytotoxic response to carboplatin but not paclitaxel or doxorubicin. In conclusion, we present data that support the need for a clinical study to evaluate the adjuvant maintenance or prescription of currently approved doses of metformin during the chemotherapeutic treatment of ovarian cancer.

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Cell-cycle dependent antagonistic interactions between paclitaxel and carboplatin in combination therapy

Cited by 27 publications

References 22 publications

The HIV reverse transcriptase inhibitor tenofovir induces cell cycle arrest in human cancer cells

The HIV reverse transcriptase inhibitor tenofovir induces cell cycle arrest in human cancer cells

In vitro effect of carboplatin, cytarabine, paclitaxel, vincristine, and low‐power laser irradiation on murine mesenchymal stem cells

Metformin, at Concentrations Corresponding to the Treatment of Diabetes, Potentiates the Cytotoxic Effects of Carboplatin in Cultures of Ovarian Cancer Cells

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