Cullin 3 Promotes Proteasomal Degradation of the Topoisomerase I-DNA Covalent Complex

Zhang, Huafeng; Tomida, Akihiro; Koshimizu, Ritsuko; Ogiso, Yasunari; Lei, Shuhong; Tsuruo, Takashi

doi:10.1158/0008-5472.can-03-2858

Cited by 60 publications

(44 citation statements)

References 36 publications

(41 reference statements)

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“…The decreased expression of CA IX in the posttreatment tumors is consistent with the inhibitor effect of CRLX101 on HIF-1α expression, which has been previously observed (7,15). CPT has been known to cause rapid degradation of Topo-I through the ubiquitin-proteasome system in tissue culture (16)(17)(18)(19)(20). Our result reveals this may also be occurring in vivo as evident by the lower staining of Topo-I in the posttreatment tumors.…”

Section: Discussionsupporting

confidence: 89%

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Clark

Wiley

Zuckerman

et al. 2016

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

145

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Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CRLX101. Both the pre-and postdosing tissue samples adjacent to tumors show no definitive evidence of either the nanoparticle or its drug payload (camptothecin, CPT) contained within the nanoparticle. Similar results are obtained from the predosing tumor samples. However, in nine of nine patients that were evaluated, CPT is detected in the tumor tissue collected 24-48 h after CRLX101 administration. For five of these patients, evidence of the intact deposition of CRLX101 nanoparticles in the tumor tissue is obtained. Indications of CPT pharmacodynamics from tumor biomarkers such as carbonic anhydrase IX and topoisomerase I by immunohistochemistry show clear evidence of biological activity from the delivered CPT in the posttreatment tumors.nanomedicine | clinical trial | gastric cancer | tumor targeting | nanoparticles N anoparticle-based experimental therapeutics are being used to deliver a variety of different drug molecules to patients with solid tumors (1). Nanoparticle delivery seeks to improve pharmacokinetic (PK) properties (e.g., enhanced solubility of the drug, increased circulation times), alter biodistribution of the drug molecules to have low amounts of drugs in nontarget tissues and increased amounts in tumors, and enhance pharmacodynamics (PD) (e.g., tunable release of the drug at the site of action in the tumor) to produce enhanced efficacy while simultaneously reducing side effects (and most importantly, introducing no new side effects due to the nanoparticle) in patients. These properties can: (i) enable drug combinations formerly prohibited by toxicity limits, (ii) enable new classes of drug delivery [for example, short interfering RNAs (siRNAs)], and (iii) provide cell-specific targeting within a tumor.Delivery of drugs to solid tumors using nanoparticle technology relies on the enhanced permeability and retention (EPR) effect. The mechanistic data regarding the EPR effect come from animal models, primarily xenografted human tumors in mice. Because these xenografted tumors poorly recapitulate the architecture of true human tumors, there is skepticism about whether or not intact nanoparticles can localize in human tumors. Radiolabeled liposomes have been used to assess tumor accumulation in humans (2, 3). In those studies, the amounts of radioactivity accumulated in tumors did correlate with the number of microvessels measured from nine patient biopsies (3). Increased microvessel density may be an indication of increasing potential for the EPR effect. Also, Davis et al. demonstrated dose-depe...

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Section: Discussionsupporting

confidence: 89%

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Clark

Wiley

Zuckerman

et al. 2016

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

145

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“…Thus, it has been suggested that the Top1 must undergo proteolysis in order for efficient Tdp1 activity [19,41,45], which is in agreement with studies demonstrating that the effectiveness of Tdp1 processing decreases as the length of the Top1 polypeptide is extended [45]. Accordingly, several studies have shown that Top1 is degraded in some cells lines following CPT treatment, suggesting that Top1 ubiquitination and degradation contribute to CPT resistance [46][47][48][49]. In addition, prevention of Top1 degradation by the proteasome inhibitors, MG132 [47] or PS-341 (clinically used) [50], results in increased sensitivity to CPT.…”

Section: Tdp1 Substratessupporting

confidence: 54%

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

144

203

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3′-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3′-end DNA alterations including 3′-phosphoglycolates and 3′-abasic sites indicating it may function as a general 3′-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.

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“…Indeed, cells proficient in this repair process are more resistant to CPT (7). In addition, overexpression of Cullin3, a component of a SCF complex, has been shown to increase ubiquitination and TOP1 down-regulation, resulting in CPT resistance (16). Furthermore, cotreatment with the proteasome inhibitor, MG132, which inhibits TOP1 down-regulation, increases tumor cell sensitivity to CPT (7).…”

Section: Introductionmentioning

confidence: 99%

ISG15 as a novel tumor biomarker for drug sensitivity

Desai¹,

Wood²,

Tsai³

et al. 2008

Molecular Cancer Therapeutics

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Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/ resistance are largely unknown. Recent studies have shown that the ubiquitin-like protein, IFN-stimulated gene 15 (ISG15), which is highly elevated in many human cancers and tumor cell lines, antagonizes the ubiquitin/ proteasome pathway. In the present study, we show that ISG15 is a determinant for CPT sensitivity/resistance possibly through its effect on proteasome-mediated repair of topoisomerase I (TOP1)-DNA covalent complexes. First, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 (major E2 for ISG15) in breast cancer ZR-75-1 cells decreased CPT sensitivity, suggesting that ISG15 overexpression in tumors could be a factor affecting intrinsic CPT sensitivity in tumor cells. Second, the level of ISG15 was found to be significantly reduced in several tumor cells selected for resistance to CPT, suggesting that altered ISG15 regulation could be a significant determinant for acquired CPT resistance. Parallel to reduced CPT sensitivity, short hairpin RNAmediated knockdown of either ISG15 or UbcH8 in ZR-75-1 cells resulted in increased proteasomal degradation of CPT-induced TOP1-DNA covalent complexes. Taken together, these results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker for CPT sensitivity.

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Cullin 3 Promotes Proteasomal Degradation of the Topoisomerase I-DNA Covalent Complex

Cited by 60 publications

References 36 publications

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

ISG15 as a novel tumor biomarker for drug sensitivity

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