Necroptosis-Inducing Rhenium(V) Oxo Complexes

Suntharalingam, Kogularamanan; Awuah, Samuel G.; Bruno, Peter M.; Johnstone, Timothy C.; Wang, Fang; Lin, Wenhan; Zheng, Yao‐Rong; Page, Julia E; Hemann, Michael T.; Lippard, Stephen J.

doi:10.1021/ja511978y

Cited by 89 publications

(86 citation statements)

References 74 publications

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“…A newly developed RNAi-based signature assay was used to further clarify the intracellular behavior of the cage. 29–33 This methodology uses a fluorescence competition assay whereby lymphoma cells that are partially infected with one of eight different short hairpin RNAs (shRNAs). Depending on the drug survival advantage or disadvantage conferred by a given shRNA, shRNA-bearing cells will either enrich or deplete relative to the uninfected population.…”

Section: Resultsmentioning

confidence: 99%

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Mechanistic studies of the anticancer activity of an octahedral hexanuclear Pt(II) cage

Zheng

Suntharalingam

Bruno

et al. 2016

Inorganica Chimica Acta

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The cellular response evoked by a hexanuclear platinum complex, Pt6L4 (1), is reported. Compound 1, a 3-nm octahedral cage formed by self-assembly of six Pt(II) centers and four 2,4,6-tris(4-pyridyl)-1,3,5-triazine ligands (L), exhibits promising in vitro potency against a panel of human cancer cell lines. Unlike classical platinum-based anticancer agents, 1 interacts with DNA in a non-covalent, intercalative manner and promotes DNA condensation. In cancer cells, 1 induces DNA damage, upregulates p53, its phosphorylated form phospho-p53 and its downstream effector, p21, as well as both apoptosis and senescence.

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Section: Resultsmentioning

confidence: 99%

“…Linkage ratios (LR) and p-values were generated as described previously. 29–33 All FACS was conducted using a FACScan (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

Mechanistic studies of the anticancer activity of an octahedral hexanuclear Pt(II) cage

Zheng

Suntharalingam

Bruno

et al. 2016

Inorganica Chimica Acta

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“…[23] This approach uses cancer cells that are partially infected with eight distinct short hairpin RNAs (shRNAs). [24] To compare similarities among 3-5 relative to other compounds,the intra-and inter-compound distances were calculated by averaging the sum of the absolute Euclidian distance between the compounds in question (Table S4). Thep attern of resistance and sensitivity of each shRNAfor the test compound is then compared to areference set of compounds with known mechanisms of action through aK -nearest neighbors based algorithm.…”

Section: Communicationsmentioning

confidence: 99%

Breast Cancer Stem Cell Potent Copper(II)–Non‐Steroidal Anti‐Inflammatory Drug Complexes

et al. 2016

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The breast cancer stem cell (CSC) potency of a series of copper(II)-phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4, selectivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis.

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“…2) (29). Necroptosis is a specialized caspase-independent pathway of programmed necrosis that relies on the signaling activity of receptor interacting serine/threonine protein kinase 1 and 3 (RIP1/ RIP3) to phosphorylate each other to form necrosomes (30,31).…”

Section: Hmgb4mentioning

confidence: 99%

Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

Awuah

Riddell

Lippard

2017

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

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Cisplatin is the most commonly used anticancer drug for the treatment of testicular germ cell tumors (TGCTs). The hypersensitivity of TGCTs to cisplatin is a subject of widespread interest. Here, we show that high-mobility group box protein 4 (HMGB4), a protein preferentially expressed in testes, uniquely blocks excision repair of cisplatin-DNA adducts, 1,2-intrastrand cross-links, to potentiate the sensitivity of TGCTs to cisplatin therapy. We used CRISPR/ Cas9-mediated gene editing to knockout the HMGB4 gene in a testicular human embryonic carcinoma and examined cellular responses. We find that loss of HMGB4 elicits resistance to cisplatin as evidenced by cell proliferation and apoptosis assays. We demonstrate that HMGB4 specifically inhibits repair of the major cisplatin-DNA adducts in TGCT cells by using the human TGCT excision repair system. Our findings also reveal characteristic HMGB4-dependent differences in cell cycle progression following cisplatin treatment. Collectively, these data provide convincing evidence that HMGB4 plays a major role in sensitizing TGCTs to cisplatin, consistent with shielding of platinum-DNA adducts from excision repair.platinum anticancer drug | testicular cancer | high-mobility group protein T esticular germ cell tumors (TGCTs) are among the few tumor types that can be clinically cured with chemotherapy owing to the potency of cisplatin (1). The introduction of cisplatin in combination chemotherapy helped advance cure rates from 5% to the current level of 90% (2). In the clinic, cisplatin is used with bleomycin and either vinblastine or etoposide to treat metastatic testicular neoplasms (3-6). The well-studied antitumor activity of cisplatin involves binding to DNA, inhibition of transcription, and induction of apoptosis (7,8). Cellular events leading to apoptosis are multifactorial and begin with uptake followed by chemical transformation of cisplatin. Following aquation, or replacement of the chloride ligands in [Pt(NH 3 ) 2 Cl 2 ] by water, the activated drug binds to DNA, generating mainly 1,2-intrastrand d(GpG) cross-links that block RNA polymerase II, ultimately signaling cell death (9-11). Recently, a cisplatinsequencing (cisplatin-seq) approach was used to confirm DNA as the target for cisplatin at the genome scale by base resolution analysis (12). High-mobility group proteins such as high-mobility group box protein 1 (HMGB1) recognize these specific cisplatin-DNA adducts and promote the toxicity of cisplatin to tumors by interfering with excision and other repair pathways (13,14).HMGB1 binds selectively to cisplatin 1,2-intrastrand d(GpG) and d(ApG) cross-links, which account for ∼90% of all platinum (Pt)-DNA adducts (15,16). Studies of the interaction of HMGB1 and other cisplatin-DNA recognition proteins such as Irx1 in yeast (17, 18) with cisplatin-modified DNA revealed bending of the DNA with attendant shielding from excision repair in vitro and subsequent sensitization of cancer cells to cisplatin treatment (13,19). Related studies showed cooperative HMGB1 and XP...

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Necroptosis-Inducing Rhenium(V) Oxo Complexes

Cited by 89 publications

References 74 publications

Mechanistic studies of the anticancer activity of an octahedral hexanuclear Pt(II) cage

Mechanistic studies of the anticancer activity of an octahedral hexanuclear Pt(II) cage

Breast Cancer Stem Cell Potent Copper(II)–Non‐Steroidal Anti‐Inflammatory Drug Complexes

Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

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