Effects of Retinoids on Cancerous Phenotype and Apoptosis in Organotypic Cultures of Ovarian Carcinoma

Guruswamy, Suresh; Lightfoot, Stan; Gold, Michael A.; Hassan, Raffit; Berlin, K. Darrell; Ivey, R. Todd; Benbrook, Doris M.

doi:10.1093/jnci/93.7.516

Cited by 74 publications

(72 citation statements)

References 41 publications

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“…These concentrations, however, are relevant to short-term (2 -3 days) monolayer culture assays. When the cells are grown within a three-dimensional extracellular matrix in organotypic cultures, and the drugs are administered at 1 Amol/L for 4 days to 2 weeks, both differentiation and apoptosis can be observed within the same cultures (1). What determines if a cell will undergo differentiation or apoptosis in response to 1 Amol/L Flex-Hets has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…This objective seems to be met by a novel class of synthetic compounds called flexible heteroarotinoids (Flex-Hets). In vitro studies showed that the Flex-Hets, called SHetA2, SHetA3, and SHetA4, induced differentiation and apoptosis in cancer cell lines and primary cultures of cancer cells (1,2). The Flex-Het compound called SHetA2 was chosen as the lead Flex-Het because it induced the highest levels of apoptosis in multiple cancer types.…”

Section: Introductionmentioning

confidence: 99%

“…This may explain the lack of conventional retinoid toxicities, such as skin irritation or teratogenicity, observed when Flex-Hets were tested in animal models designed to specifically test for these toxicities (3,5). The only retinoid activity retained by Flex-Hets is their ability to induce differentiation or reverse the cancerous phenotype (1). The major difference between Flex-Hets and retinoids is the ability of FlexHets to induce potent apoptotic activity in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Liu

Hannafon

Gill

et al. 2007

Molecular Cancer Therapeutics

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Flex-Het drugs induce apoptosis in multiple types of cancer cells, with little effect on normal cells. This apoptosis occurs through the intrinsic mitochondrial pathway accompanied by generation of reactive oxygen species (ROS). The objective of this study was to determine if direct or indirect targeting of mitochondria is responsible for the differential sensitivities of cancer and normal cells to Flex-Hets. Mitochondrial effects and apoptosis were measured using JC-1 and Annexin V-FITC dyes with flow cytometry. Bcl-2, Bcl-x L , and Bax were measured by Western blot. Flex-Hets induced mitochondrial swelling and apoptosis in ovarian cancer cell lines but had minimal to no effects in a variety of normal cell cultures, including human ovarian surface epithelium. Effects on inner mitochondrial membrane (IMM) potential were variable and did not occur in normal cells. Two different antioxidants, administered at concentrations shown to quench intracellular and mitochondrial ROS, did not alter Flex-Het -induced mitochondrial swelling, loss of IMM potential, or apoptosis. Inhibition of protein synthesis with cycloheximide also did not prevent FlexHet mitochondrial or apoptosis effects. Bcl-2 and Bcl-x L levels were decreased in an ovarian cancer cell line but increased in a normal culture, whereas Bax expression was unaffected by Flex-Hets treatment. In conclusion, ROS seems to be a consequence rather than a cause of mitochondrial swelling. The differential induction of apoptosis in cancer versus normal cells by Flex-Hets involves direct targeting of mitochondria associated with alterations in the balance of Bcl-2 proteins. This mechanism does not require IMM potential, ROS generation, or protein synthesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Liu

Hannafon

Gill

et al. 2007

Molecular Cancer Therapeutics

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“…30,31 While monolayer cultures are suited for evaluation of growth rates, they do not recapitulate interactions with similar and different cell types of cells and with extracellular matrix. We placed the collagen bed at the air-medium interface since it more closely resembles normal ovary structure and discriminates tridimensional growth of normal OSE cells from that of immortalized OSE or malignant ovarian carcinoma lines.…”

Section: Discussionmentioning

confidence: 99%

Reversion of transformed phenotype in ovarian cancer cells by intracellular expression of anti folate receptor antibodies

et al. 2003

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The a-folate receptor (FR) is selectively overexpressed in 90% of nonmucinous ovarian carcinomas, whereas no expression is detectable in normal ovarian surface epithelium (OSE). Indirect evidence suggests that FR expression is associated with tumor progression and affects cell proliferation. To evaluate better the role of FR, we developed an approach based on intracellular expression of single-chain (sc) antibodies (intrabody) to downmodulate membrane expression of FR in ovary cancer cells. IGROV-1 and SKOV3 ovarian carcinoma cell lines were transfected with an anti-FR intrabody. Transfectants and parental cells were tested for FR, integrins and anti-FR intrabody expression by fluorescence-activated cell sorting (FACS), reverse transcription and polymerase chain reaction (RT-PCR) and/or immunoblotting. Cell growth characteristics and adhesion properties were evaluated in liquid, semisolid and organotypic cultures. The anti-FR scFv inhibited FR expression from 60 to 99%. At physiological concentrations of folate, proliferation varied directly as a function of FR expression. FR downmodulation was accompanied by reduced colonyforming ability in soft agar, morphological change of the cells, significant enhanced adhesion to laminin or Matrigel, a twoto three-fold increase in a6b4 integrin expression, and a marked reduction in laminin production. In three-dimensional organotypic cultures, anti-FR intrabody-transfected IGROV1 cells grew as a single-ordered layer, reminiscent of normal OSE growth in vivo. In conclusion, the anti-FR intrabody reverses the transformed phenotype in ovary cancer cells and may provide an efficient means to inhibit selectively the growth of these cells.

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“…Various synthetic retinoids, including RA, have shown promise for the treatment and prevention of several cancers, including carcinoma of the breast (Veronesi et al, 1999;Dragnev et al, 2000;Guruswamy et al, 2001). Numerous groups, including ours, have found that retinoids potently inhibit the growth of breast cancer cell lines (Zhu et al, 1997;Rosenauer et al, 1998;Wang et al, 2000), and others have reported the capacity of retinoids to inhibit mammary carcinogenesis in animal models (Anzano et al, 1994;Moon and Constantinou, 1997).…”

Section: Introductionmentioning

confidence: 85%

Retinoic acid-induced growth arrest of MCF-7 cells involves the selective regulation of the IRS-1/PI 3-kinase/AKT pathway

et al. 2003

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Effects of Retinoids on Cancerous Phenotype and Apoptosis in Organotypic Cultures of Ovarian Carcinoma

Abstract: At clinically achievable concentrations, all retinoids tested decrease the growth fraction, induce differentiation and apoptosis. Induction of MUC1 expression is implicated in the mechanisms of action.

Cited by 74 publications

References 41 publications

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Reversion of transformed phenotype in ovarian cancer cells by intracellular expression of anti folate receptor antibodies

Retinoic acid-induced growth arrest of MCF-7 cells involves the selective regulation of the IRS-1/PI 3-kinase/AKT pathway

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