ROS-induced nanotherapeutic approach for ovarian cancer treatment based on the combinatorial effect of photodynamic therapy and DJ-1 gene suppression

Schumann, Canan; Taratula, Olena; Khalimonchuk, Oleh; Palmer, Amy L.; Cronk, Lauren M.; Jones, Carson V.; Escalante, Cesar A.; Taratula, Oleh

doi:10.1016/j.nano.2015.07.005

Cited by 37 publications

(49 citation statements)

References 48 publications

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“…42 Moreover, our previous reports confirmed that nanoplatforms equipped with LHRH peptide can efficiently deliver siRNA molecules to LHRH-positive cancer cells both in vitro and in vivo . 21–25 Following the modification steps, we determined hydrodynamic size of the constructed siRNA nanoplatform, which turned out to be 147.8 ± 11.0 nm (Figure 3D). The LHRH-targeted, nanoplatform loaded with the scrambled siRNA, did not compromise viability (Figure 3C), proliferation (Figure S2) and DJ-1 mRNA expression (Figure S3) of ovarian cancer cells, indicating that the prepared siRNA delivery system is non-toxic.…”

Section: Resultsmentioning

confidence: 99%

“…The obtained data is consistent with the previous reports, which demonstrated that DJ-1 protein suppression in cancer cells can effectively enhance the efficacy of the anti-cancer therapies. 21, 46 For example, Zhang et al . reported that the sensitivity of adriamycin resistance MCF-7 breast cancer cells to chemotherapy was significantly improved following DJ-1 knockdown.…”

Section: Resultsmentioning

confidence: 99%

“…demonstrated that the therapeutic efficacy of the photodynamic therapy for ovarian cancer treatment was substantially enhanced through the siRNA-mediated inhibition of the DJ-1 protein and this effect was more pronounced in A2780/AD cells than in ES2 cells, wherein former cells are characterized by higher basal levels of DJ-1 protein. 21 …”

Section: Resultsmentioning

confidence: 99%

“…This data is in agreement with our previously published observation of a dramatic increase in endogenous ROS in the DJ-1-overexpressing A2780/AD (Adriamycin-resistant) cells upon the protein’s depletion in combination with ROS-inducing photodynamic therapy. 21 …”

Section: Resultsmentioning

confidence: 99%

“…21 Briefly all cell lines were seeded in T-25 flask at a cell density of 20 × 10 5 and incubated overnight at 37°C. Afterward the media was removed and 3.6 mL of fresh media along with 0.4 mL of DJ-1 siRNA-NP was added to each flask (total volume 4 mL; final siRNA concentration = 1 μM).…”

Section: Methodsmentioning

confidence: 99%

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Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

et al. 2016

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We report an efficient therapeutic modality for platinum resistant ovarian cancer based on siRNA-mediated suppression of a multifunctional DJ-1 protein that is responsible for the proliferation, growth, invasion, oxidative stress and overall survival of various cancers. The developed therapeutic strategy can work alone or in concert with a low dose of the first line chemotherapeutic agent cisplatin, to elicit a maximal therapeutic response. To achieve an efficient DJ-1 knockdown, we constructed the polypropylenimine dendrimer-based nanoplatform targeted to LHRH receptors overexpressed on ovarian cancer cells. The quantitative PCR and western immunoblotting analysis, revealed that the delivered DJ-1 siRNA downregulated the expression of targeted mRNA and corresponding protein by more than 80% in various ovarian cancer cells. It was further demonstrated that siRNA-mediated DJ-1 suppression dramatically impaired proliferation, viability and migration of the employed ovarian cancer cells. Finally, the combinatorial approach led to the most pronounced therapeutic response in all the studied cell lines, outperforming both siRNA-mediated DJ-1 knockdown and cisplatin treatment alone. It is noteworthy that the platinum-resistant cancer cells (A2780/CDDP) with the highest basal level of DJ-1 protein are most susceptible to the developed therapy and this susceptibility declines with decreasing basal levels of DJ-1. Finally, we interrogate the molecular underpinnings of the DJ-1 knockdown effects in the treatment of the ovarian cancer cells. By using various experimental techniques, it was revealed that DJ-1 depletion: (1) decreases the activity of the Akt pathway, thereby reducing cellular proliferation, migration and increasing the antiproliferative effect of cisplatin on ovarian cancer cells; (2) enhances the activity of p53 tumor suppressor protein therefore restoring cell cycle arrest functionality and upregulating the Bax-caspase pathway, triggering cell death; and (3) weakens the cellular defense mechanisms against inherited oxidative stress thereby increasing toxic intracellular radicals and amplifying the reactive oxygen species created by the administration of cisplatin.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

et al. 2016

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Photo‐Induced Charge‐Variable Conjugated Polyelectrolyte Brushes Encapsulating Upconversion Nanoparticles for Promoted siRNA Release and Collaborative Photodynamic Therapy under NIR Light Irradiation

Zhao

et al. 2017

Adv Funct Materials

104

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Combination of photodynamic therapy (PDT) with small interfering RNA (siRNA) therapy has become a major strategy in cancer treatment for enhancing anticancer efficacy. However, developing nanoplatform that can promote siRNA release and collaborate with efficient PDT under NIR light irradiation is still a big challenge. Photo‐induced charge‐variable conjugated polyelectrolyte brushes encapsulating upconversion nanoparticles (UCNP@CCPEB) as an efficient nanoplatform are reported. Cationic conjugated polyelectrolyte brush (CCPEB) is synthesized through quaternary ammoniation of N‐functionalized polyfluorene brush by photodegradable 2‐nitrobenzyl‐2‐bromoacetate. CCPEB with abundant positive charges and intrinsic photosensitizer (PS) performance is good for integrating siRNA carrier and PS into one molecule. The obtained CCPEB next encapsulates upconversion nanoparticle for realizing its NIR light excitation. Agarose gel electrophoresis experiments show that UCNP@CCPEB present good stability and excellent siRNA‐loading capacity (1 mol UCNP@CCPEB to at least 32.5 mol siRNA). Under 980 nm light irradiation, UCNP@CCPEB exhibit efficient single oxygen production for PDT. Concurrently, the photoresponsive cationic side‐chain of CCPEB turns into zwitterionic chain and thus accelerates its siRNA release to 80%. In vitro and in vivo experiments show that the successful A549 tumor suppression is achieved by UCNP@CCPEB/siPlk1 complex under 980 irradiation. It is envisioned that UCNP@CCPEB can serve as an efficient platform for combining various phototherapies together.

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Au Nanoclusters and Photosensitizer Dual Loaded Spatiotemporal Controllable Liposomal Nanocomposites Enhance Tumor Photodynamic Therapy Effect by Inhibiting Thioredoxin Reductase

Gao

Zheng

Gao

et al. 2017

Adv Healthcare Materials

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Photodynamic therapy (PDT) is a minimally invasive therapeutic procedure of tumors with high selectivity and low side effect. However, it is usually not efficient in long-lasting tumor control. One of the main reasons is tumor cells develop some protective mechanisms that help them to deal with oxidative stress in the environment. The thioredoxin system in cancer is an important antioxidant defense system. Au nanoclusters could effectively inhibit thioredoxin reductase (TrxR) in tumor cell cytoplasm. Herein, Au nanoclusters and photosensitizer Chlorine 6 (Ce6) are co-loaded in spatiotemporal controllable liposomal nanocomposites. pH responsive molecule inserted in lipid bilayer greatly contributes to the instability of the lipid membrane in lysosomal at low pH environment. Then the payloads can rapidly release into cytoplasm. Au nanoclusters effectively inhibit TrxR in cytoplasm and enhance the photodynamic-induced intracellular reactive oxygen-free radical concentration, improving the effect of PDT. Breast cancer is chosen as a tumor model and the Au nanoclusters and photosensitizer co-loaded liposomal nanocomposites are studied to improve the effect of PDT both in vitro and in vivo, and its corresponding mechanism is investigated. This study develops a new application of gold nanoclusters and provides a new train of thoughts for enhancing the effect of PDT.

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ROS-induced nanotherapeutic approach for ovarian cancer treatment based on the combinatorial effect of photodynamic therapy and DJ-1 gene suppression

Cited by 37 publications

References 48 publications

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer

Photo‐Induced Charge‐Variable Conjugated Polyelectrolyte Brushes Encapsulating Upconversion Nanoparticles for Promoted siRNA Release and Collaborative Photodynamic Therapy under NIR Light Irradiation

Au Nanoclusters and Photosensitizer Dual Loaded Spatiotemporal Controllable Liposomal Nanocomposites Enhance Tumor Photodynamic Therapy Effect by Inhibiting Thioredoxin Reductase

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