Molecular mechanism of phenoxodiol‐induced apoptosis in ovarian carcinoma cells

Alvero, Ayesha B.; O’Malley, D.; Brown, David A.; Kelly, Graham; Garg, Manish; Chen, Wei; Rutherford, Thomas J.; Mor, Gil

doi:10.1002/cncr.21633

Cited by 84 publications

(101 citation statements)

References 14 publications

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“…These studies have shown that in some cancers phenoxodiol appears to be strong enough to work on its own as a monotherapy. However, one of the major benefits of phenoxodiol is its ability to sensitize cancer cells to the antitumor effects of conventional chemotherapeutics [137]. It has been found that cancer cells that have become resistant to the effects of conventional chemo-therapeutics, phenoxodiol could restore chemosensitivity [138].…”

Section: Genistein Analogues and Related Studiesmentioning

confidence: 99%

Multi-targeted therapy of cancer by genistein

Banerjee¹,

Li²,

Wang³

et al. 2008

Cancer Letters

560

383

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Soy isoflavones have been identified as dietary components having an important role in reducing the incidence of breast and prostate cancers in Asian countries. Genistein, the predominant isoflavone found in soy products, has been shown to inhibit the carcinogenesis in animal models. There is a growing body of experimental evidence showing that the inhibition of human cancer cell growth by genisteinis mediated via the modulation of genes that are related to the control of cell cycle and apoptosis. It has been shown that genistein inhibits the activation of NF-κB and Akt signaling pathways, both of which are known to maintain a homeostatic balance between cell survival and apoptosis. Moreover, genistein antagonizes estrogen-and androgen-mediated signaling pathways in the processes of carcinogenesis. Furthermore, genistein has been found to have antioxidant properties, and shown to be a potent inhibitor of angiogenesis and metastasis. Taken together, both in vivo and in vitro studies have clearly shown that genistein, one of the major soy isoflavones, is a promising agent for cancer chemoprevention and further suggest that it could be an adjunct to cancer therapy by virtue of its effects on reversing radioresistance and chemoresistance. In this review, we attempt to provide evidence for these preventive and therapeutic effects of genistein in a succinct manner highlighting comprehensive state-of-the-art knowledge regarding its multi-targeted biological and molecular effects in cancer cells.

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Section: Genistein Analogues and Related Studiesmentioning

confidence: 99%

Multi-targeted therapy of cancer by genistein

Banerjee¹,

Li²,

Wang³

et al. 2008

Cancer Letters

560

383

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“…Cells (2×10 5 ) were activated by adding 10 µg/mL anti-CD3 and 5 µg/mL anti-CD28 and 20 U/mL interleukin-2 per well. Cells were incubated at 37°C in 5% CO2 in a humidified incubator for 4 to 5 days until large numbers of large spherical aggregates or bursts of lymphocytes were observed.…”

Section: In Vitro Activation Of T Cellsmentioning

confidence: 99%

“…1,2 Phenoxodiol has been referred to as a pan-cancer drug, 3 causing apoptosis in cancer cell lines and murine cancer models via both intrinsic and extrinsic pathways. [4][5][6][7][8][9][10][11][12][13][14] Plasma membrane electron transport (PMET) has been shown to be a target of phenoxodiol in several studies with cancer cell lines. 3,13,15 PMET consists of an outer membrane (surface) NADH-oxidoreductase, redox-recycling plasma membrane ubiquinone and an inner membrane NADH-oxidoreductase.…”

Section: Introductionmentioning

confidence: 99%

The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells

Herst¹,

Davis²,

Neeson³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundThe redox-active isoflavene anti-cancer drug, phenoxodiol, has previously been shown to inhibit plasma membrane electron transport and cell proliferation and promote apoptosis in a range of cancer cell lines and in anti-CD3/anti-CD28-activated murine splenocytes but not in non-transformed WI-38 cells and human umbilical vein endothelial cells. Design and MethodsWe determined the effects of phenoxodiol on plasma membrane electron transport, MTT responses and viability of activated and resting human T cells. In addition, we evaluated the effect of phenoxodiol on the viability of leukemic cell lines and primary myeloid and lymphoid leukemic blasts. ResultsWe demonstrated that phenoxodiol inhibited plasma membrane electron transport and cell proliferation (IC50 46 µM and 5.4 µM, respectively) and promoted apoptosis of rapidly proliferating human T cells but did not affect resting T cells. Phenoxodiol also induced apoptosis in T cells stimulated in HLA-mismatched allogeneic mixed lymphocyte reactions. Conversely, non-proliferating T cells in the mixed lymphocyte reaction remained viable and could be restimulated in a third party mixed lymphocyte reaction, in the absence of phenoxodiol. In addition, we demonstrated that leukemic blasts from patients with primary acute myeloid leukemia (n=22) and acute lymphocytic leukemia (n=8) were sensitive to phenoxodiol. The lymphocytic leukemic blasts were more sensitive than the myeloid leukemic blasts to 10 µM phenoxodiol exposure for 24h (viability of 23±4% and 64±5%, respectively, p=0.0002). ConclusionsThe ability of phenoxodiol to kill rapidly proliferating lymphocytes makes this drug a promising candidate for the treatment of pathologically-activated lymphocytes such as those in acute lymphoid leukemia, or diseases driven by T-cell proliferation such as autoimmune diseases and graft-versus-host disease.

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“…We have identified the core molecular structure required for benzopyran compounds to exert these functions and using this pharmacophore, we have created firstand second-generation drugs that exhibit significant activity against several types of cancer, including ovarian, both in vitro and in vivo. Phenoxodiol and triphendiol are first-generation compounds that have been shown to induce caspase-mediated cell death (20)(21)(22)(23)(24)(25). In ovarian cancer, phenoxodiol acts as a chemosensitizer and thus lowers the IC 50 for standard-of-care chemotherapy agents (20-22, 26, 27).…”

Section: Introductionmentioning

confidence: 99%

TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

Alvero

Heaton²,

Lima

et al. 2016

Molecular Cancer Therapeutics

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Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer and is responsible for its high mortality. Studies have shown that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. We have developed a library of super-benzopyran analogues to generate potent compounds that can induce cell death in chemoresistant cancer stem cells.

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Molecular mechanism of phenoxodiol‐induced apoptosis in ovarian carcinoma cells

Cited by 84 publications

References 14 publications

Multi-targeted therapy of cancer by genistein

Multi-targeted therapy of cancer by genistein

The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells

TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

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