Novel Classes of Dimer Antitumour Drug Candidates

Chow, Larry M.C.; Chan, Tak Hang

doi:10.2174/138161209787315576

Cited by 24 publications

(23 citation statements)

References 74 publications

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“…Concentric rings of replicating GMCs comparable with wild type were retained in treated larvae. It has been previously reported that artemisinin and curcumin acts via NFκB , as well as ROS pathways , and showed that elevated ROS generation caused apoptosis of AK‐5 (a rat histiocyte macrophage tumor line) after curcumin treatment, whereas it was reduced in normal cell populations under the same treatment . In our study, the ROS hyperactivity on eighth and ninth day tumorous brain was decreased by 10th day after individual and combinatorial treatments of these drugs.…”

Section: Discussionsupporting

confidence: 56%

Artemisinin and Curcumin inhibit Drosophila brain tumor, prolong life span, and restore locomotor activity

2014

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Deletion of tumor suppressor gene, lethal(2)giant larvae [l(2)gl], leads to brain tumor in Drosophila melanogaster at larval stage of development and severe brain dysplasia in mice. We have studied the effect of two potential antitumor drugs artemisinin and curcumin in the perspective of inhibiting l(2)gl brain tumor. Efficacies of these drugs are characterized morphologically by measuring brain sizes of untreated and treated larvae on the basis of tumor inhibition and anatomically by looking at the cellular patterning via antibody staining of the third instar Drosophila larval brains. Behavioral experiments were done in form of locomotion to correlate tumor inhibition with the revival of brain function and longevity assays to assess general health span. It was observed that both drugs show antitumor properties individually and in combination when larvae were treated with these drugs. We also found evidence for reactive oxygen speciesmediated action of these drugs. Both the drugs when treated individually or together show better median life span and locomotory response. Although the efficacies of various treatments varied, overall, the positive effects of artemisinin and curcumin demonstrate a potential applicability of these drugs against brain tumor in higher organisms. It also paves a way for a simpler model system for screening such natural products for antitumor property. V C 2014 IUBMB Life, 66(7): [496][497][498][499][500][501][502][503][504][505][506] 2014

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Section: Discussionsupporting

confidence: 56%

Artemisinin and Curcumin inhibit Drosophila brain tumor, prolong life span, and restore locomotor activity

2014

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“…The rationale for the development of dimeric species as pharmaceuticals derives from the possible binding of the dimeric ligand at two distinct binding sites either on a single receptor or at defined sites on two separate monomers of a dimeric protein (26). We have designed Lys01 as a dimeric form of CQ, with the spacer N,N-bis(2-aminoethyl)methylamine 5 as the connector between two CQ moieties.…”

Section: Discussionmentioning

confidence: 99%

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

McAfee¹,

Zhang²,

Samanta³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

357

313

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Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.cell death | stress responses | cancer cell survival | drug resistance | antimalarials A utophagy, the sequestration of organelles and proteins in autophagic vesicles (AVs) and degradation of this cargo through lysosomal fusion (1), allows tumor cells to survive metabolic and therapeutic stresses (2-5). Therapy-induced autophagy is a key resistance mechanism to many anticancer agents (6), and autophagy levels are increased in most cancers (7). Chloroquine (CQ; Fig. 1, compound 1) derivatives block autophagy by impairing lysosomal function (3,8,9). Studies in multiple mouse models of malignancy have demonstrated that autophagy inhibition with CQ derivatives augments the efficacy of a variety of anticancer agents. Clinical trials combining cancer therapies with hydroxychloroquine (HCQ; Fig. 1), have been launched, and preliminary results indicate these combinations have activity (6). However, pharmacokinetic (PK)-pharmacodynamic (PD) studies conducted in patients receiving HCQ for cancer therapy have indicated that the high micromolar concentrations of HCQ required to inhibit autophagy in vitro are inconsistently achieved in humans (10). There is an unmet need to develop more potent inhibitors of autophagy.The design and synthesis of dimeric analogs of CQ that exploit the thermodynamic advantages imparted by polyvalency (11, 12) has been previously studied in the context of malaria (13-15). The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14). Subsequently, a seri...

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“…Polyvalent molecules have the potential to yield nonlinear, multifold potency against their respective targets compared to their corresponding monomers (18, 19). With the goal of generating new autophagy inhibitors with better potency, tolerability, and anticancer efficacy than HCQ, we used logical medicinal chemistry approaches to generate a series of new dimeric compounds containing modified core elements of HCQ, CQ and the anti-schistosomal drug lucanthone (Miracil D) (20).…”

Section: Introductionmentioning

confidence: 99%

Disruption of Autophagic Degradation with ROC-325 Antagonizes Renal Cell Carcinoma Pathogenesis

Carew

Espitia

Zhao

et al. 2017

Clinical Cancer Research

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Purpose Although autophagy plays important roles in malignant pathogenesis and drug resistance, there are few clinical agents that disrupt this pathway and the potential therapeutic benefit of autophagy inhibition remains undetermined. We used medicinal chemistry approaches to generate a series of novel agents that inhibit autophagic degradation. Experimental Design ROC-325 was selected as a lead compound for further evaluation. Comprehensive in vitro and in vivo studies were conducted to evaluate the selectivity, tolerability, and efficacy of ROC-325 in preclinical models of renal cell carcinoma (RCC) with HCQ serving as a comparator. Markers of autophagy inhibition and cell death were evaluated in tumor specimens. Results ROC-325 exhibited superior in vitro anticancer effects than the existing autophagy inhibitor hydroxychloroquine in 12 different cancer cell lines with diverse genetic backgrounds. Focused studies of the mechanism of action and efficacy of ROC-325 in RCC cells showed that drug treatment induced hallmark characteristics of autophagy inhibition including accumulation of autophagosomes with undegraded cargo, lysosomal deacidification, p62 stabilization, and disruption of autophagic flux. Subsequent experiments showed that ROC-325 antagonized RCC growth and survival in an ATG5/7-dependent manner, induced apoptosis, and exhibited favorable selectivity. Oral administration of ROC-325 to mice bearing 786-0 RCC xenografts was well tolerated, significantly more effective at inhibiting tumor progression than HCQ, and inhibited autophagy in vivo. Conclusions Our findings demonstrate that ROC-325 has superior preclinical anticancer activity compared to HCQ and support the clinical investigation of its safety and preliminary efficacy in patients with RCC and other autophagy-dependent malignancies.

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Novel Classes of Dimer Antitumour Drug Candidates

Cited by 24 publications

References 74 publications

Artemisinin and Curcumin inhibit Drosophila brain tumor, prolong life span, and restore locomotor activity

Artemisinin and Curcumin inhibit Drosophila brain tumor, prolong life span, and restore locomotor activity

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

Disruption of Autophagic Degradation with ROC-325 Antagonizes Renal Cell Carcinoma Pathogenesis

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