Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death

Wang, Xiaoya; Wei, Sanhua; Zhao, Yong; Shi, Changhong; Liu, Peijuan; Zhang, Caiqin; Lei, Yingfeng; Zhang, Bo; Bai, Bing; Huang, Yong; Hai, Zhang

doi:10.1016/j.canlet.2016.10.034

Cited by 90 publications

(90 citation statements)

References 36 publications

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“…We found that overexpression of FOXK2 inhibited the proliferation, migration and invasion of ccRCC cells, whereas knockdown of FOXK2 promoted these aspects. 40,41 Our apoptosis assays showed that overexpression of FOXK2 remarkably increased the percentage of apoptotic ccRCC cells, whereas knockdown of FOXK2 did not significantly decrease the percentage of these cells. 18 Unlike previous studies, our results showed that in both FOXK2 knocked-down and overexpressed cells, no statistically significant changes were detected in the percentage of G0/G1 phases and S phase cells.…”

Section: Discussionmentioning

confidence: 87%

FOXK2 suppresses the malignant phenotype and induces apoptosis through inhibition of EGFR in clear‐cell renal cell carcinoma

Zhang

et al. 2018

Intl Journal of Cancer

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Forkhead box K2 (FOXK2) belongs to the forkhead box transcription factor family. Recent studies have revealed that FOXK2 plays essential roles in cancer cell proliferation and survival. However, the biological function of FOXK2 in renal cell carcinoma remains unexplored. In our study, we demonstrated that FOXK2 mRNA and protein levels were decreased in clear-cell renal cell carcinoma (ccRCC) tissues compared to those in corresponding non-tumor renal tissues, and decreased FOXK2 levels were associated with poor prognosis in ccRCC patients after nephrectomy. FOXK2 suppressed proliferation, migration and invasion capabilities of ccRCC cells and induced cellular apoptosis in vitro. Moreover, we found that FOXK2 overexpression inhibited xenograft tumor growth and promoted apoptosis in vivo. Genome-wide transcriptome profiling using FOXK2 overexpressed 769-P cells revealed that the epidermal growth factor receptor (EGFR) was a potential downstream gene of FOXK2. Overexpression of EGFR is able to rescue the inhibited proliferation capacity and the enhanced apoptosis capacity due to the overexpression of FOXK2 in 769-P cells. Collectively, our results indicate that FOXK2 inhibits the malignant phenotype of ccRCC and acts as a tumor suppressor possibly through the inhibition of EGFR.

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Section: Discussionmentioning

confidence: 87%

FOXK2 suppresses the malignant phenotype and induces apoptosis through inhibition of EGFR in clear‐cell renal cell carcinoma

Zhang

et al. 2018

Intl Journal of Cancer

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“…Itraconazole inhibits AKT (protein kinase B)/mechanistic target of rapamycin (mTOR) signaling in human umbilical vein endothelial cells (HUVECs), glioblastoma, endometrial carcinoma (EC) and melanoma cells (10)(11)(12)(13)(14). Inhibition of Hedgehog signaling was observed in basal cell carcinoma, medulloblastoma, pleural mesothelioma, breast cancer and melanoma cells (9,(14)(15)(16)(17), but not in EC cells (13). Inhibition of Wnt/β-catenin signaling was observed in basal cell and examined in melanoma cells (14).…”

Section: Preclinical Datamentioning

confidence: 99%

“…Inhibition of Wnt/β-catenin signaling was observed in basal cell and examined in melanoma cells (14). Itraconazole also induced autophagic cell death in medulloblastoma cells as well as in breast cancer cells (12,17), and suppressed lymphangiogenesis in lung carcinoma cells (18).…”

Section: Preclinical Datamentioning

confidence: 99%

Repurposing itraconazole as an anticancer agent

et al. 2017

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Abstract. Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including reversing chemoresistance mediated by P-glycoprotein, modulating the signal transduction pathways of Hedgehog, mechanistic target of rapamycin and Wnt/β-catenin in cancer cells, inhibiting angiogenesis and lymphangiogenesis, and possibly interfering with cancer-stromal cell interactions. Clinical trials have suggested the clinical benefits of itraconazole monotherapy for prostate cancer and basal cell carcinoma, as well as the survival advantage of combination chemotherapy for relapsed non-small cell lung, ovarian, triple negative breast, pancreatic and biliary tract cancer. As drug repurposing is cost-effective and timesaving, a review was conducted of preclinical and clinical data focusing on the anticancer activity of itraconazole, and discusses the future directions for repurposing itraconazole as an anticancer agent.

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“…Abnormal activation of Hh signaling has been observed in breast cancer and implicated in drug resistance [66,67]. Itraconazole, a clinically used antifungal drug which is repurposed for cancer therapy, has been demonstrated to be able to kill cancer cells via inhibiting Hh signaling [31] and inducing apoptosis and cell cycle arrest [32].…”

Section: Crosstalk Between Hedgehog Signaling Pathway and Autophagymentioning

confidence: 99%

“…A recent study showed that inhibition of Hh signaling by itraconazole induced cytotoxicity, apoptosis, tumor shrinkage, and autophagy in breast cancer in vitro cell lines or in vivo mouse models. Moreover, inhibiting autophagy by 3-MA or ATG5 silencing attenuated itraconazole-induced cell death, suggesting that Hh inhibition-induced autophagy played a role in autophagic cell death [66]. In addition, another study demonstrated that itraconazole induced autophagy in glioblastoma cell lines U87 and C6, via repressing AKT1–mTOR signaling.…”

Section: Crosstalk Between Hedgehog Signaling Pathway and Autophagymentioning

confidence: 99%

Hedgehog Signaling Pathway and Autophagy in Cancer

Zeng

2018

IJMS

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Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.

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Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death

Cited by 90 publications

References 36 publications

FOXK2 suppresses the malignant phenotype and induces apoptosis through inhibition of EGFR in clear‐cell renal cell carcinoma

FOXK2 suppresses the malignant phenotype and induces apoptosis through inhibition of EGFR in clear‐cell renal cell carcinoma

Repurposing itraconazole as an anticancer agent

Hedgehog Signaling Pathway and Autophagy in Cancer

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