Anti-Cancer Potential of a Novel SERM Ormeloxifene

Gara, Rishi K.; Sundram, Vasudha; Chauhan, Subhash C.; Jaggi, Meena

doi:10.2174/09298673113209990197

Cited by 35 publications

(20 citation statements)

References 43 publications

(81 reference statements)

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“…Ormeloxifene (ORM) is a non-hormonal, non-steroidal oral contraceptive molecule (18). Recent studies suggested that ORM may be effective in inhibiting breast cancer, head and neck cancer, and chronic myeloid leukemia cells (18). Moreover, ORM is reported to have an excellent therapeutic index and is safe for chronic administration (19).…”

Section: Introductionmentioning

confidence: 99%

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

et al. 2015

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The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine (GEM). Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene (ORM), has potent anti-cancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ORM inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ORM with GEM at the molecular level. ORM caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NFκB, p-AKT and Cyclin D1. ORM potentiated the anti-tumorigenic effect of GEM by 75% in PDAC xenograft mice. Further, ORM depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ORM in combination with GEM restored the tumor suppressor miR-132, and inhibited stromal cell infiltration into the tumor tissues. Additionally, invasiveness of tumor cells co-cultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ORM treatment alone or in combination with GEM. We propose that ORM has high therapeutic index and in a combination therapy with GEM it possesses great promise as a treatment of choice for PDAC/pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

et al. 2015

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“…Ormeloxifene (ORM), a non-steroidal molecule which is widely used as an oral contraceptive in humans [14, 15], can be repurposed for cancer treatment. This is a potent agent that has been widely shown to act upon several important molecular targets in cancer [16]. ORM has shown greater protective effects on Salmonella strains TA97a, TA98, TA100 and TA102 than Tamoxifen [17].…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle formulation of ormeloxifene for pancreatic cancer

et al. 2015

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Pancreatic cancer is the fourth most prevalent cancer with about an 85% mortality rate; thus, an utmost need exists to discover new therapeutic modalities that would enhance therapy outcomes of this disease with minimal or no side effects. Ormeloxifene (ORM), a synthetic molecule, has exhibited potent anti-cancer effects through inhibition of important oncogenic and proliferation signaling pathways. However, the anti-cancer efficacy of ORM can be further improved by developing its nanoformulation, which will also offer tumor specific targeted delivery. Therefore, we have developed a novel ORM encapsulated poly(lactic-co-glycolic acid) nanoparticle (NP) formulation (PLGA-ORM NP). This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). Because of its facile composition, this novel formulation is compatible with antibody/aptamer conjugation to achieve tumor specific targeting. The particle size analysis of this PLGA-ORM formulation (~ 100 nm) indicates that this formulation can preferentially reach and accumulate in tumors by the Enhanced Permeability and Retention (EPR) effect. Cellular uptake and internalization studies demonstrate that PLGA-ORM NPs escape lysosomal degradation, providing efficient endosomal release to cytosol. PLGA-ORM NPs showed remarkable anti-cancer potential in various pancreatic cancer cells (HPAF-II, BxPC-3, Panc-1, MiaPaca) and a BxPC-3 xenograft mice model resulting in increased animal survival. PLGA-ORM NPs suppressed pancreatic tumor growth via suppression of Akt phosphorylation and expression of MUC1, HER2, PCNA, CK19 and CD31. This study suggests that the PLGA-ORM formulation is highly efficient for the inhibition of pancreatic tumor growth and thus can be valuable for the treatment of pancreatic cancer in the future.

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“…[423] Moreover, it possesses anticancer activity against a number of other cancers such as ovarian, head and neck cancer, and chronic myloid leukemia. [9] Here, we demonstrate the combination of CC with GN in ER −ve (MDA MB-231/MDA MB-468) and ER +ve (MCF-7/T-47D) cell lines employing nontumorigenic HMEC MCF-10A as control. GN is a phytoestrogen, categorized under isoflavones, and has binding affinity with ERs.…”

Section: Discussionmentioning

confidence: 84%

“…It has the ability to interact with both ERα and ERβ but has higher affinity for the former (8%) compared to latter (3%). [9] We demonstrated its novel antineoplastic potential in MCF-7/MDA MB-231 cells where it was found that CC induces G0/G1 arrest and caspase-dependent apoptosis in these cells. [567] We further demonstrated the enhanced antineoplasticity of CC when administered with resveratrol and curcumin.…”

Section: Discussionmentioning

confidence: 99%

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Genistein synergizes centchroman action in human breast cancer cells

et al. 2016

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Objectives:Despite the progress in the diagnosis and treatment of breast cancer, it remains a major health problem in women. Natural flavones along with chemotherapeutic agents enhance therapeutic response and minimize toxicity of chemical agents. Centchroman (CC) colloquially called as ormeloxifene, is a nonsteroidal oral contraceptive categorized as selective estrogen receptor modulator with anti-breast cancer activity. Genistein (GN), an isoflavone found mainly in soy products possesses anti-cancerous potential against a number of cancers including breast. The present study aims at investigating the combination of CC and GN in human breast cancer cell lines (HBCCs).Materials and Methods:Cytotoxic effect of CC and GN separately and in combination were assessed by sulforhodamine B (SRB) assay in MDA MB-231, MDA MB-468, MCF-7, T-47D HBCCs, and nontumorigenic human mammary epithelial cell (HMEC) MCF-10A. The drug interaction was analyzed using CompuSyn software through which combination index and dose reduction index were generated.Results:Combination of CC plus GN exerts significantly higher cytotoxicity compared to each drug per se in HBCCs, whereas HMEC-MCF-10A remains unaffected.Conclusion:On an overall basis, the drugs in combination enhanced cell killing in malignant cells. Therefore, the combination of CC with GN may offer a novel approach for the breast cancer.

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Anti-Cancer Potential of a Novel SERM Ormeloxifene

Cited by 35 publications

References 43 publications

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

Nanoparticle formulation of ormeloxifene for pancreatic cancer

Genistein synergizes centchroman action in human breast cancer cells

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