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Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancer.

ABSTRACT: Metastatic ovarian cancer (OvCa) frequently recurs due to chemoresistance, highlighting the need for nonoverlapping combination therapies that mechanistically synergize to eradicate residual disease. Photodynamic therapy (PDT), a photochemistry-based cytotoxic modality, sensitizes ovarian tumors to platinum agents and biologics and has shown clinical promise against ovarian carcinomatosis. We introduce a three-dimensional (3D) model representing adherent ovarian micrometastases and high-throughput quantitative imaging methods to rapidly screen the order-dependent effects of combining benzoporphyrin-derivative (BPD) monoacid A-based PDT with low-dose carboplatin. 3D ovarian micronodules grown on Matrigel were subjected to BPD-PDT either before or after carboplatin treatment. We developed custom fluorescence image analysis routines to quantify residual tumor volume and viability. Carboplatin alone did not eradicate ovarian micrometastases at a dose of 400 mg/m2, leaving surviving cores that were nonsensitive or impermeable to chemotherapy. BPD-PDT (1.25 ?mol/L·J/cm2) created punctate cytotoxic regions within tumors and disrupted micronodular structure. Treatment with BPD-PDT prior to low-dose carboplatin (40 mg/m2) produced a significant synergistic reduction [P<0.0001, analysis of covariance (ANCOVA)] in residual tumor volume [0.26; 95% confidence interval (95% CI), 0.19-0.36] compared with PDT alone (0.76; 95% CI, 0.63-0.92) or carboplatin alone (0.95; 95% CI, 0.83-1.09), relative to controls. This synergism was not observed with the reverse treatment order. Here, we demonstrate for the first time the use of a 3D model for micrometastatic OvCa as a rapid and quantitative reporter to optimize sequence and dosing regimens of clinically relevant combination strategies. This approach combining biological modeling with high-content imaging provides a platform to rapidly screen therapeutic strategies for a broad array of metastatic tumors.

SUBMITTER: Rizvi I

PROVIDER: S-EPMC3057933 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancer.

Rizvi Imran I Celli Jonathan P JP Evans Conor L CL Abu-Yousif Adnan O AO Muzikansky Alona A Pogue Brian W BW Finkelstein Dianne D Hasan Tayyaba T

Cancer research 20101109 22

Metastatic ovarian cancer (OvCa) frequently recurs due to chemoresistance, highlighting the need for nonoverlapping combination therapies that mechanistically synergize to eradicate residual disease. Photodynamic therapy (PDT), a photochemistry-based cytotoxic modality, sensitizes ovarian tumors to platinum agents and biologics and has shown clinical promise against ovarian carcinomatosis. We introduce a three-dimensional (3D) model representing adherent ovarian micrometastases and high-throughp ...[more]

PMID: 21062986

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Project description:BACKGROUND:Epithelial ovarian cancers (EOCs) comprises the majority of malignant ovarian neoplasms. Combination treatment with chemotherapeutic agents seems to be a promising strategy in ovarian cancer (OVCA) patients in order to overcome drug resistance. In this in vitro study, we investigated the therapeutic efficacy of verteporfin (VP) alone and in combination with cisplatin (CDDP), carboplatin (CP) and paclitaxel (Taxol). The main objectives of this study are to determine the nature of interactions between VP and CDDP/CP/Taxol and to understand the mechanism of action of VP in OVCA cells. METHODS:The efficacy of VP on cell proliferation, cytotoxicity, invasion and clonogenic capacity was assayed in CDDP-sensitive (COV504, OV-90) and CDDP-resistant (A2780Cis) cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using MTT assay and Cell Viability Blue assay. The effects of drugs on the metabolic functions were studied using matrigel invasion assay and clonogenic assay. Immunoblot analysis was carried out to investigate changes in YAP and cell cycle genes. Changes in the cytokines due to drug treatments were analyzed using a cytokine array. RESULTS:Treatment with VP inhibited cell proliferation, invasion and increased cytotoxicity of OVCA cells. We observed that VP chemosensitized CDDP-resistant cells, even at lower doses. When added either in constant or non-constant ratios, VP produced synergistic effects in combination with CDDP/CP/Taxol. A cytokine array identified upregulation of cytokines in OVCA cells that were inhibited by VP treatment. CONCLUSIONS:Either in cisplatin-resistant cell lines or cisplatin-sensitive cell lines, VP proves to be more efficient in inhibiting cell proliferation and inducing cytotoxicity. Our results suggest that novel combinations of VP with CDDP or CP or Taxol might be an attractive therapeutic strategy to enhance OVCA chemosensitivity. The fact that lower doses of VP are effective in chemosensitizing the CDDP-resistant cells, might ultimately lead to the development of an innovative combination therapy for the treatment of OVCA patients.

Project description:Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that poses a serious global public health threat. Due to the high incidence of adverse reactions associated with conventional treatment regimens, there is an urgent need for better alternative therapies. CpG oligodeoxynucleotides (CpG ODNs) are synthetic oligodeoxyribonucleotide sequences. They can induce a Th1-type immune response by stimulating Toll-like receptors (TLRs) in mammalian immune cells, thus killing Mtb. However, due to the negative charge and easy degradation of CpG ODNs, it is necessary to deliver them into cells using nanomaterials. PCN-224 (hereinafter referred to as PCN), as a metal-organic framework based on zirconium ions and porphyrin ligands, not only has the advantage of high drug loading capacity, but also the porphyrin molecule in it is a type of photosensitizer, which allows these nanocomposites to play a role in photodynamic therapy (PDT) while delivering CpG ODNs. In addition, since Mtb mainly exists in macrophages, targeting anti-TB agents to macrophages is helpful to improve the anti-TB effect. Phosphatidylserine (PS) is a biological membrane phospholipid that is normally found on the inner side of cell membranes in, for example, plant and mammalian cells. When apoptosis occurs, PS can flip from the inner side of the cell membrane to the surface of the cell membrane, displaying a specific "eat-me" signal that can be recognized by specific receptors on macrophages. Therefore, we can use this macrophage-targeting property of PS to construct bio-inspired targeted drug delivery systems. In this study, we constructed PCN-CpG@PS nanocomposites. PCN-CpG@PS, combining PDT and immunotherapy, is designed to target macrophages at the site of a lesion and kill latent Mtb. We physically characterized the nanocomposites and validated their bactericidal ability in vitro and their ability to stimulate the immune system in vivo. The results demonstrated that the targeted nanocomposites have certain in vitro antituberculosis efficacy with good safety.

Dataset Information

Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancer.

Publications

Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancer.

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