Basic and Clinical Studies on the Treatment of Malignant Tumors With a Fibroblasts Inhibiting Agent, Chloroquine

Kimura, Ikuo; Ota, Zensuke; Asano, Keiichi; Kageyama, Hiroshi; Shibuya, Koichi; Kodani, Hidenari; Matsuura, Ryozo; Tsuchida, Junichiro; Sezaki, T; Hiraoka, Toshinobu; Himei, Hitomi; Moritani, Yoshiaki; Mori, Toshio; Yamana, Masatoshi

doi:10.2169/naika.52.213

Cited by 3 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, fibroblasts treated with Cav-1 siRNA behave has been known since 1963 that chloroquine selectively targets the fibroblast compartment in both xenograft models and human tumors, resulting in striking reductions in tumor growth. [39][40][41][42][43][44][45] Interest in chloroquine has also recently re-emerged, as a preventative therapeutic for DCIS patients, in a new clinical trial known as PINC (Preventing Invasive Breast Neoplasia with Cholorquine) (See clinicaltrials.gov/show/NCT01023477). Since a loss of stromal Cav-1 in DCIS patients is a strong predictor of progression to invasive breast cancer, 8 choloroquine's anti-cancer efficacy in DCIS patients may be due to its ability to rescue the expression of Cav-1 in the stromal fibroblast compartment via the inhibition of autophagy.…”

Section: Discussionmentioning

confidence: 99%

Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors

et al. 2010

View full text Add to dashboard Cite

Loss of stromal caveolin 1 (Cav-1) is a novel biomarker for cancer-associated fibroblasts that predicts poor clinical outcome in breast cancer and DCIS patients. We hypothesized that epithelial cancer cells may have the ability to drive Cav-1 downregulation in adjacent normal fibroblasts, thereby promoting the cancer associated fibroblast phenotype. To test this hypothesis directly, here we developed a novel co-culture model employing (i) human breast cancer cells (MCF7), and (ii) immortalized fibroblasts (hTERT-BJ1), which are grown under defined experimental conditions. Importantly, we show that co-culture of immortalized human fibroblasts with MCF7 breast cancer cells leads to Cav-1 downregulation in fibroblasts. These results were also validated using primary cultures of normal human mammary fibroblasts co-cultured with MCF7 cells. In this system, we show that Cav-1 downregulation is mediated by autophagic/lysosomal degradation, as pre-treatment with lysosome-specific inhibitors rescues Cav-1 expression. Functionally, we demonstrate that fibroblasts co-cultured with MCF7 breast cancer cells acquire a cancer associated fibroblast phenotype, characterized by Cav-1 downregulation, increased expression of myofibroblast markers and extracellular matrix proteins, and constitutive activation of TGFβ/Smad2 signaling. siRNA-mediated Cav-1 downregulation mimics several key changes that occur in co-cultured fibroblasts, clearly indicating that a loss of Cav-1 is a critical initiating factor, driving stromal fibroblast activation during tumorigenesis. As such, this co-culture system can now be used as an experimental model for generating "synthetic" cancer associated fibroblasts (CAFs). More specifically, these "synthetic" CAFs could be used for drug screening to identify novel therapeutics that selectively target the Cav-1-negative tumor micro-environment. Our findings also suggest that chloroquine, or other autophagy/lysosome inhibitors, may be useful as anti-cancer agents, to therapeutically restore the expression of stromal Cav-1 in cancer associated fibroblasts. We discuss this possibility, in light of the launch of a new clinical trial that uses chloroquine to treat DCIS patients: PINC (Preventing Invasive Breast Neoplasia with Cholorquine) [See http://clinicaltrials.gov/show/NCT01023477].

show abstract

Section: Discussionmentioning

confidence: 99%

Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors

et al. 2010

View full text Add to dashboard Cite

show abstract

The Chloroquine Mystery

Knox¹

1966

Arch Dermatol

View full text Add to dashboard Cite

Nitroxoline shows antimyeloma activity by targeting the TRIM25/p53 axle

Mao

Zhang

et al. 2017

Anti-Cancer Drugs

View full text Add to dashboard Cite

The aim of this study was to identify the most potent quinoline-based anti-infectives for the treatment of multiple myeloma (MM) and to understand the molecular mechanisms. A small-scale screen against a panel of marketed quinoline-based drugs was performed in MM cell lines. Cell apoptosis was examined by flow cytometry. Anti-MM activity was also evaluated in nude mice. Western blotting was performed to investigate mechanisms. Nitroxoline (NXQ) was the most effective in suppressing MM cell proliferation. NXQ induced more than 40% MM cell apoptosis within 24 h and potentiated anti-MM activities of current major drugs including doxorubicin and lenalidomide. This finding was shown by activation of caspase-3, a major executive apoptotic enzyme, and by inactivation of PARP, a major enzyme in DNA damage repair. NXQ also suppressed prosurvival proteins Bcl-xL and Mcl-1. Moreover, NXQ suppressed the growth of myeloma xenografts in nude mice models. In the mechanistic study, NXQ was found to downregulate TRIM25, a highly expressed ubiquitin ligase in MM. Notably, NXQ upregulated tumor suppressor p53, but not PTEN. Furthermore, overexpression of TRIM25 decreased p53 protein. This study indicated that the long-term use of anti-infective NXQ has potential for MM treatment by targeting the TRIM25/p53 axle.

show abstract

Basic and Clinical Studies on the Treatment of Malignant Tumors With a Fibroblasts Inhibiting Agent, Chloroquine

Cited by 3 publications

References 0 publications

Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors

Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors

The Chloroquine Mystery

Nitroxoline shows antimyeloma activity by targeting the TRIM25/p53 axle

Contact Info

Product

Resources

About