Overcoming cisplatin resistance by mTOR inhibitor in lung cancer

Wu, Chunjing; Wangpaichitr, Medhi; Feun, Lynn G.; Kuo, Marcus Tien; Robles, Carlos; Lampidis, Théodore J.; Savaraj, Niramol

doi:10.1186/1476-4598-4-25

Cited by 104 publications

(43 citation statements)

References 35 publications

(25 reference statements)

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“…CCI-779 also has substantial single-agent activity in certain haematologic malignancies such as mantle cell lymphoma [91]. In addition, rapamycin and rapalogues have demonstrated efficacy in combination with other chemotherapeutics [92–94]. …”

Section: Therapeutic Targeting Of Cap-dependent Translational Complexmentioning

confidence: 99%

Targeting of protein translation as a new treatment paradigm for prostate cancer

Ramamurthy¹,

Ramalingam²,

Kwegyir-Afful³

et al. 2017

Current Opinion in Oncology

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Purpose of review This overview will summarize some of the developments in the area of protein translation, including as they relate to the therapeutic targeting of prostate cancer. Recent findings Translational control, mediated by the rate-limiting eukaryotic translation initiation factor 4E (eIF4E), drives selective translation of several oncogenic proteins, thereby contributing to tumor growth, metastasis, and treatment resistance in various cancers, including prostate cancer. As an essential regulatory hub, several oncogenic hyperactive signaling pathways appear to converge on eIF4E to promote tumorigenesis. Several approaches that target the eIF4E-dependent protein translation network are being actively studied, and it is likely that some may ultimately emerge as promising anticancer therapeutics. Summary An array of inhibitors has shown promise in targeting specific components of the translational machinery in several pre-clinical models of prostate cancer. It is hoped that some of these approaches may ultimately have relevance in improving the clinical outcomes of patients with advanced prostate cancer.

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Section: Therapeutic Targeting Of Cap-dependent Translational Complexmentioning

confidence: 99%

Targeting of protein translation as a new treatment paradigm for prostate cancer

Ramamurthy¹,

Ramalingam²,

Kwegyir-Afful³

et al. 2017

Current Opinion in Oncology

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“…mTOR inhibitors have shown their efficacy in enhancing the effects of chemotherapeutics agents in various malignancies (25–29). We have recently demonstrated that the mTOR inhibitor, rapamycin, potentiates the anti-proliferative effects of paclitaxel in endometrial cancer cell lines (30).…”

Section: Introductionmentioning

confidence: 99%

Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway

Hanna

Zhou

Malloy

et al. 2012

Gynecologic Oncology

122

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Objectives To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines. Methods ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed after exposure to paclitaxel and metformin. Cell cycle progression was assessed by flow cytometry. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the effect of metformin/paclitaxel on the mTOR pathway. Results Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC50 values of 1–5 nM and 5–10 nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5 mM) resulted in a significant synergistic anti-proliferative effect in both cell lines (Combination Index <1). Metformin induced G1 arrest in both cell lines. Paclitaxel alone or in combination with metformin resulted in predominantly G2 arrest. Metformin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Metformin stimulated AMPK phosphorylation and decreased phosphorylation of the S6 protein. In contrast, paclitaxel inhibited AMPK phosphorylation in the ECC-1 cell line and induced phosphorylation of S6 in both cell lines. Treatment with metformin and paclitaxel resulted in decreased phosphorylation of S6 in both cell lines but only had an additive effect on AMPK phosphorylation in the ECC-1 cell line. Conclusions Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. This combination may be a promising targeted therapy for endometrial cancer.

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“…Recently, it has been shown that mTOR1-S6K1 signaling controls the transcription of FANCD2 [42, 43]. In this regard, we have previously shown that arginine deprivation by ADI-PEG20 leads to inhibition of mTOR [5] while cisplatin treatment can result in mTOR activation [9, 44]in an attempt to evade cell death. Thus, it is possible that inhibition of mTOR by arginine deprivation is a possible mechanism(s) why FANCD2 is decreased.…”

Section: Discussionmentioning

confidence: 99%

Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin

Savaraj

et al. 2015

Oncotarget

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Loss of argininosuccinate synthetase (ASS) expression in melanoma makes these tumor cells vulnerable to arginine deprivation. Pegylated arginine deiminase (ADI-PEG20) which degrades arginine to citrulline and ammonia has been used clinically and partial responses and stable disease have been noted with minimal toxicity. In order to improve the therapeutic efficacy of ADI-PEG20, we have combined ADI-PEG20 with a DNA damaging agent, cisplatin. We have shown that the combination of the two drugs together significantly improved the therapeutic efficacy when compared to ADI-PEG20 alone or cisplatin alone in 4 melanoma cell lines, regardless of their BRAF mutation. In-vivo study also exhibited the same effect as in-vitro with no added toxicity to either agent alone. The underlying mechanism is complex, but increased DNA damage upon arginine deprivation due to decreased DNA repair proteins, FANCD2, ATM, and CHK1/2 most likely leads to increased apoptosis. This action is further intensified by increased proapoptotic protein, NOXA, and decreased antiapoptotic proteins, SURVIVIN, BCL2 and XIAP. The autophagic process which protects cells from apoptosis upon ADI-PEG20 treatment also dampens upon cisplatin administration. Thus, the combination of arginine deprivation and cisplatin function in concert to kill tumor cells which do not express ASS without added toxicity to normal cells.

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Overcoming cisplatin resistance by mTOR inhibitor in lung cancer

Cited by 104 publications

References 35 publications

Targeting of protein translation as a new treatment paradigm for prostate cancer

Targeting of protein translation as a new treatment paradigm for prostate cancer

Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway

Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin

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