Research progress of hydroxychloroquine and autophagy inhibitors on cancer

Shi, Tingting; Yu, Xiaoxu; Yan, Lei; Xiao, Hongtao

doi:10.1007/s00280-016-3197-1

Cited by 114 publications

(103 citation statements)

References 73 publications

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“…It has some dose-sensitive effects, and a number of molecular modifications, such as HCQ nanocarriers, have been used to improve its pharmacokinetic and pharmacodynamics properties, in order to reduce the undesirable side effect of the drug [10]. HCQ’s inhibitory interaction with the lysosome could be contributing to defective lysosomes function, which has been known to cause lysosomal storage disease [62].…”

Section: Discussionmentioning

confidence: 99%

“…HCQ is the only clinically-approved autophagy inhibitor, but the pharmacodynamic studies indicate that higher doses of HCQ up to 1200 mg/d produce only modest inhibition in vivo and can be inconsistent [10]. It also fails to inhibit autophagy in acidic environments around 6.5, due to the reduction in the cellular uptake of the drug in these environments [10,50].…”

Section: New Potent Autophagy Inhibitorsmentioning

confidence: 99%

“…It also fails to inhibit autophagy in acidic environments around 6.5, due to the reduction in the cellular uptake of the drug in these environments [10,50]. The limitation of HCQ’s ability to function in vivo creates a demand for the production of more potent autophagy inhibitors.…”

Section: New Potent Autophagy Inhibitorsmentioning

confidence: 99%

“…Multiple studies have shown that some tumors may be autophagy-dependent, meaning that their survival is dependent on their ability to use the autophagy pathway as a source of nutrient replenishment [9]. These findings have led to the idea of using autophagic inhibitors as a new form of cancer therapy treatment [8,10]. …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors

Chude

Amaravadi

2017

IJMS

300

153

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Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic.

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Section: Discussionmentioning

confidence: 99%

Section: New Potent Autophagy Inhibitorsmentioning

confidence: 99%

Section: New Potent Autophagy Inhibitorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors

Chude

Amaravadi

2017

IJMS

300

153

View full text Add to dashboard Cite

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“…Different classes of antimalarial drugs display direct or adjuvant activity against cancer cell lines, are known as sensitivity reversers of resistant tumor cell lines or inhibitors of drug resistance development, or have synergistic action with known anticancer drugs . Although their exact mode of action against cancer is still not completely understood, various mechanisms have been proposed …”

Section: Introductionmentioning

confidence: 99%

SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

et al. 2018

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We report the synthesis of SAHAquines and related primaquine (PQ) derivatives. SAHAquines are novel hybrid compounds that combine moieties of suberoylanilide hydroxamic acid (SAHA), an anticancer agent with weak antiplasmodial activity, and PQ, an antimalarial drug with low antiproliferative activity. The preparation of SAHAquines is simple, cheap, and high yielding. It includes the following steps: coupling reaction between primaquine and a dicarboxylic acid monoester, hydrolysis, a new coupling reaction with O‐protected hydroxylamine, and deprotection. SAHAquines 5 a–d showed significant reduction in cell viability. Among the three human cancer cell lines (U2OS, HepG2, and MCF‐7), the most responsive were the MCF‐7 cells. The antibodies against acetylated histone H3K9/H3K14 in MCF‐7 cells revealed a significant enhancement following treatment with N‐hydroxy‐N′‐{4‐[(6‐methoxyquinolin‐8‐yl)amino]pentyl}pentanediamide (5 b). Ethyl (2E)‐3‐({4‐[(6‐methoxyquinolin‐8‐yl)amino]pentyl}carbamoyl)prop‐2‐enoate (2 b) and SAHAquines were the most active compounds against both the hepatic and erythrocytic stages of Plasmodium parasites, some of them at sub‐micromolar concentrations. The results of our research suggest that SAHAquines are promising leads for new anticancer and antimalarial agents.

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Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome‐lysosome Fusion in NSCLC

Guo,

Zhou,

Wang

et al. 2024

Advanced Science

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Aloperine (ALO), a quinolizidine‐type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non‐small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome‐1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO‐induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti‐PD‐L1/TGF‐β bispecific antibody in inhibiting LLC‐derived subcutaneous tumor models. Thus, ALO is first identified as a novel late‐stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.

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Research progress of hydroxychloroquine and autophagy inhibitors on cancer

Abstract: Additional mechanistic studies of HCQ in preclinical models are still required in order to answer these questions whether HCQ actually inhibits autophagy in non-selective tumors and whether the extent of inhibition would be sufficient to alter chemotherapy or radiotherapy sensitivity.

Cited by 114 publications

References 73 publications

Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors

Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors

SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome‐lysosome Fusion in NSCLC

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