Transition Metal Intercalators as Anticancer Agents—Recent Advances

Deo, K.; Pages, Benjamin J.; Ang, Dale L.; Gordon, Christopher P.; Aldrich‐Wright, Janice R.

doi:10.3390/ijms17111818

Cited by 70 publications

(33 citation statements)

References 83 publications

(96 reference statements)

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“…Vanadium is a transition metal that can be found in both cationic and anionic forms with six oxidation states (Deo et al, 2016). Most significantly, several of these vanadium compounds prevent and inhibit the growth of various types of cancer in multiple in vitro and in vivo assays (Kowalski et al, 2017;Leon et al, 2015;Rozzo et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Sodium metavanadate (NaVO 3 [V(+5)]) and bis(acetylacetonate)oxidovanadium [V(+4)] have apoptotic-inducing activity and enter the cell through facilitated diffusion and ionic channels depending on their oxidative status (Imtiaz et al, 2015), but in biological media vanadium compounds mainly exist in the +4 and/or +5 oxidative status ( Figure 1) (Al-Majed, 2007;Crans et al, 2010;Deo, Pages, Ang, Gordon, & Aldrich-Wright, 2016;Leon et al, 2015;Mutlu, Cristy, Graves, Hooth, & Waidyanatha, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Vanadium compounds and cellular death mechanisms in the A549 cell line: The relevance of the compound valence

Guerrero-Palomo

Rendón-Huerta

Montaño

et al. 2018

J of Applied Toxicology

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Non‐small lung cell carcinoma has a high morbidity and mortality rates. The elective treatment for stage III and IV is cisplatinum that conveys serious toxic side effects. Vanadium compounds are metal molecules with proven antitumor activity that depends on its valence. Therefore, a better understanding of the mechanism of action of vanadium compounds is required. The aim of our study was to investigate the mechanisms of cell death induced by sodium metavanadate (NaVO3 [V(+5)]) and vanadyl sulfate (VOSO4 [(+4)]), both of which have reported apoptotic‐inducing activity. We exposed the A549 cell line to various concentrations (0‐100 μM) and to different exposure times to each compound and determined the cell viability and expression of caspases, reactive oxygen species (ROS) production, Bcl2, Bax, FasL and NO. Our results showed that neither compounds modified the basal expression of caspases or pro‐ and anti‐apoptotic proteins. The only change observed was the 12‐ and 14‐fold significant increase in ROS production induced by NaVO3 and VOSO4, respectively, at 100 μm concentrations after 48 hours. Our results suggest that classical apoptotic mechanisms are not related to the cell death induced by the vanadium compounds evaluated here, and showed that the higher ROS production was induced by the [(+4)] valence compound. It is possible that the difference will be secondary to its higher oxidative status and thus higher ROS production, which leads to higher cell damage. In conclusion, our results suggest that the efficacy of the cell death mechanisms induced by vanadium compounds differ depending on the valence of the compound.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vanadium compounds and cellular death mechanisms in the A549 cell line: The relevance of the compound valence

Guerrero-Palomo

Rendón-Huerta

Montaño

et al. 2018

J of Applied Toxicology

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“…The Rh-PPO mechanism is reminiscent of lesion-specific DNA glycosylases that probe destabilized regions of the genome and, upon binding, flip the mismatched base into the enzyme active site (31,32). Indeed, the first-generation metalloinsertor, similar to a glycosylase, was able to photochemically cleave DNA at a mismatch site (31,33).…”

Section: Discussionmentioning

confidence: 99%

Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells

Bailis

Weidmann

Mariano

et al. 2017

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

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The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)] 2+(Rh-PPO). We find that Rh-PPO binding induces a lesion that triggers the DNA damage response (DDR). DDR activation results in cellcycle blockade and inhibition of DNA replication and transcription. Significantly, the lesion induced by Rh-PPO is not repaired in MMRdeficient cells, resulting in selective cytotoxicity. The Rh-PPO mechanism is reminiscent of DNA repair enzymes that displace mismatched bases, and is differentiated from other DNA-targeted chemotherapeutics such as cisplatin by its potency, cellular mechanism, and selectivity for MMR-deficient cells.cancer | DNA damage response | metalloinsertor | mismatch repair D NA mismatch repair (MMR) corrects mismatched base pairs that arise from replication errors and is involved in the recognition and processing of DNA damage induced by chemotherapeutics such as cis-diamminedichloroplatinum(II) (cisplatin) (1, 2). Loss of function of the MMR pathway is an important mechanism for mutation generation and predisposition to cancer. Lynch syndrome, an inherited condition characterized by susceptibility to develop colon cancer, results from germline inactivation of the MMR pathway (3). Somatic loss of function of the MMR pathway occurs in 10-25% of cancers of the colon, endometrium, ovary, and other tissue types (3-5). MMR-deficient cancer cells display a 100-to 1,000-fold increase in mutation rate and are resistant to many DNA-targeted chemotherapeutics (6, 7). Because of this, patients with MMR-deficient cancers do not benefit from standard of care therapy including cisplatin (8, 9). New therapies that target these patient populations are needed.We have previously described a class of octahedral rhodium(III) complexes, termed metalloinsertors, as a strategy toward the targeted therapy of MMR-deficient cancers. These compounds contain a sterically expansive 5,6-chrysenequinone diimine ligand (chrysi; Fig. 1A) that binds with high specificity to DNA mismatches, independent of sequence context (10). X-ray crystal structures demonstrate that the chrysi ligand is capable of inserting at the mismatch from the DNA minor groove; this binding mode, called metalloinsertion, maintains duplex stacking but displaces the mismatched bases into the major or minor groove (11, 12). As a consequence, metalloinsertor binding preferentially inhibits DNA synthesis and growth of cell lines that are MMR-deficient (13-15). Structureactivity relationship studies reveal that compound selectivity and cell potency...

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“…The mechanism of action of CDDP is multifaceted [101,102] . Besides forming intra-and interstrand cross-links within DNA, which prevent repair mechanisms and lead to apoptosis [103][104][105] , additional mechanisms include generation of reactive oxygen species, increased susceptibility to pro-apoptotic signals, and interference with mitochondrial activity and calcium signaling [106] .…”

Section: Cisplatinmentioning

confidence: 99%