Chloroquine Combined With Rapamycin Arrests Tumor Growth in a Patient-derived Orthotopic Xenograft (PDOX) Mouse Model of Dedifferentiated Liposarcoma

Masaki, Noriyuki; Aoki, Yusuke; Kubota, Yutaro; Obara, Koya; Miyazaki, Jun; Hoffman, Robert M.

doi:10.21873/invivo.12997

Cited by 5 publications

(7 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As summarized in Table 1 (Ref. [35,50,52,53,55,57,58,60,61,63,66,67,[69][70][71]73,[75][76][77][78][79][80][83][84][85][86][87]), the roles of autophagy induced by rapamycin, temsirolimus as well as everolimus have not been shown to be consistent in preclinical studies. The primary role of the autophagic flux induced in response to everolimus is cytoprotective with a clinical trial performed by Haas et al [63] supporting the clinical utility of the autophagy inhibitor, HCQ, to improve everolimus clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…The same research group [85] also tested rapamycin in combination with CQ in vivo using patient-derived orthotopic xenograft mice models of dedifferentiated liposarcoma. The combination showed a marked tumor growth arrest as compared to each drug alone, together with increased apoptosis induced as showed by the TUNEL assay, more firmly arguing for a cytoprotective role for the autophagic process.…”

Section: Rapamycin and Autophagymentioning

confidence: 99%

See 1 more Smart Citation

The Cytoprotective and Cytotoxic Functions of Autophagy in Response to mTOR Inhibitors

Elshazly,

Elzahed,

Gewirtz

2024

Front. Biosci. (Landmark Ed)

View full text Add to dashboard Cite

The inhibitors of mammalian target of rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range of clinical utility; however, as is inevitably the case with other chemotherapeutic agents, resistance development constrains their effectiveness. One putative mechanism of resistance is the promotion of autophagy, which is a direct consequence of the inhibition of the mTOR signaling pathway. Autophagy is primarily considered to be a cytoprotective survival mechanism, whereby cytoplasmic components are recycled to generate energy and metabolic intermediates. The autophagy induced by everolimus and temsirolimus appears to play a largely protective function, whereas a cytotoxic function appears to predominate in the case of rapamycin. In this review we provide an overview of the autophagy induced in response to mTOR inhibitors in different tumor models in an effort to determine whether autophagy targeting could be of clinical utility as adjuvant therapy in association with mTOR inhibition.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Rapamycin and Autophagymentioning

confidence: 99%

The Cytoprotective and Cytotoxic Functions of Autophagy in Response to mTOR Inhibitors

Elshazly,

Elzahed,

Gewirtz

2024

Front. Biosci. (Landmark Ed)

View full text Add to dashboard Cite

show abstract

“…We previously established a patient-derived orthotopic xenograft (PDOX) mouse model of dedifferentiated liposarcoma and showed that the combination of CQ and RAPA was effective in inhibiting tumor growth by inducing apoptosis (5). Excessive accumulation of autophagosomes has been shown to induce apoptosis in cancer cells (9, 10).…”

Section: Discussionmentioning

confidence: 99%

“…Well-differentiated liposarcomas (WDLS) can become dedifferentiated after repeated recurrence (3,4). We previously observed that the combination of the mTORinhibitor rapamycin (RAPA) and the anti-malarial drug chloroquine (CQ) had synergistic efficacy in a patient-derived orthotopic xenograft (PDOX) mouse model of dedifferentiated liposarcoma, with a high number of apoptosis-positive cancer cells (5).…”

mentioning

confidence: 99%

Targeting Autophagy With the Synergistic Combination of Chloroquine and Rapamycin as a Novel Effective Treatment for Well-differentiated Liposarcoma

Masaki

Aoki

Obara

et al. 2023

Cancer Genomics Proteomics

Self Cite

View full text Add to dashboard Cite

Background/Aim: Liposarcoma is a type of softtissue sarcoma arising from fat tissue. It is relatively common among soft-tissue sarcomas. Chloroquine (CQ), an antimalarial drug, can inhibit autophagy and induce apoptosis in cancer cells. Rapamycin (RAPA) is an inhibitor of mTOR. The combination of RAPA and CQ is a strong inhibitor of autophagy. Previously, we showed that the combination of RAPA and CQ was effective against a de-differentiated liposarcoma patient-derived orthotopic xenograft (PDOX) mouse model. In the present study, we investigated the mechanism of efficacy of the combination of RAPA and CQ to target autophagy in a welldifferentiated liposarcoma (WDLS) cell line in vitro. Materials and Methods: The human WDLS cell line 93T449 was used. The WST-8 assay was used to test the cytotoxicity of RAPA and CQ. Western blotting was used to detect microtubule-associated protein light chain 3-II (LC3-II) which is a component of autophagosomes. Immunostaining of LC3-II was also performed for autophagosome analysis. Τhe TUNEL assay was used to detect apoptotic cells, and apoptosis-positive cells were counted in three randomly selected microscopic fields for statistical validation. Results: RAPA alone and CQ alone inhibited the viability of 93T449 cells. The combination of RAPA and CQ inhibited 93T449 cell viability significantly more than either drug alone and increased the number of autophagosomes which led to extensive apoptosis. Conclusion: The combination of RAPA and CQ increased the number of autophagosomes which led to apoptosis in 93T449 WDLS cells, suggesting novel effective treatment for this recalcitrant cancer by targeting autophagy.

show abstract

“…In MG63 osteosarcoma cells, CQ enhances apoptotic cell death promoted by mTOR inhibitor rapamycin (RAPA) by blocking the activity of downstream molecules of Akt/mTOR pathway 4E-BP1 and p70S6k, increasing the expression of autophagy-related proteins LC3-II and Atg12-Atg5, and decreasing the p62 level [78]. Although CQ was not effective as a single treatment, CQ/RAPA exposure induced apoptosis via the overaccumulation of autophagosomes in well-differentiated human liposarcoma (WDLS) 93T449 cells [79] and arrested the growth of dedifferentiated liposarcoma in mice bearing patient-derived orthotopic xenografts (DDLS PDOX) [103].…”

Section: Chloroquine and Pi3k/akt/mtor Inhibitorsmentioning

confidence: 99%

Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment

Agalakova

2024

IJMS

View full text Add to dashboard Cite

Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ), the compounds with recognized ability to suppress autophagy, have been tested in experimental works and in clinical trials as adjuvant therapy for the treatment of tumors of different origin to increase the efficacy of cytotoxic agents. Such a strategy can be effective in overcoming the resistance of cancer cells to standard chemotherapy or anti-angiogenic therapy. This review presents the results of the combined application of CQ/HCQ with conventional chemotherapy drugs (doxorubicin, paclitaxel, platinum-based compounds, gemcitabine, tyrosine kinases and PI3K/Akt/mTOR inhibitors, and other agents) for the treatment of different malignancies obtained in experiments on cultured cancer cells, animal xenografts models, and in a few clinical trials. The effects of such an approach on the viability of cancer cells or tumor growth, as well as autophagy-dependent and -independent molecular mechanisms underlying cellular responses of cancer cells to CQ/HCQ, are summarized. Although the majority of experimental in vitro and in vivo studies have shown that CQ/HCQ can effectively sensitize cancer cells to cytotoxic agents and increase the potential of chemotherapy, the results of clinical trials are often inconsistent. Nevertheless, the pharmacological suppression of autophagy remains a promising tool for increasing the efficacy of standard chemotherapy, and the development of more specific inhibitors is required.

show abstract

Chloroquine Combined With Rapamycin Arrests Tumor Growth in a Patient-derived Orthotopic Xenograft (PDOX) Mouse Model of Dedifferentiated Liposarcoma

Cited by 5 publications

References 43 publications

The Cytoprotective and Cytotoxic Functions of Autophagy in Response to mTOR Inhibitors

The Cytoprotective and Cytotoxic Functions of Autophagy in Response to mTOR Inhibitors

Targeting Autophagy With the Synergistic Combination of Chloroquine and Rapamycin as a Novel Effective Treatment for Well-differentiated Liposarcoma

Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment

Contact Info

Product

Resources

About