Retinoids are vitamin A derivatives that regulate crucial biological processes such as cellular proliferation, apoptosis, and differentiation. The use of natural retinoids in cancer therapy is ...limited due to their toxicity and the acquired resistance by cancer cells. Therefore, synthetic retinoids were developed, such as the atypical adamantyl retinoid ST1926 that provides enhanced bioavailability and reduced toxicity. We have assessed the in vitro and in vivo antitumor properties and mechanism of action of ST1926 in targeting cancer stem‐like cells population of human prostate cancer (PCa) cell lines, DU145 and PC3, and mouse PCa cell lines, PLum‐AD and PLum‐AI. We demonstrated that ST1926 substantially reduced proliferation of PCa cells and induced cell cycle arrest, p53‐independent apoptosis, and early DNA damage. It also decreased migration and invasion of PCa cells and significantly reduced prostate spheres formation ability in vitro denoting sufficient eradication of the self‐renewal ability of the highly androgen‐resistant cancer stem cells. Importantly, ST1926 potently inhibited PCa tumor growth and progression in vivo. Our results highlight the potential of ST1926 in PCa therapy and warrant its clinical development.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Acute myeloid leukemia (AML) is one of the most frequent types of blood malignancies. It is a complex disorder of undifferentiated hematopoietic progenitor cells. The majority of patients generally ...respond to intensive therapy. Nevertheless, relapse is the major cause of death in AML, warranting the need for novel treatment strategies. Retinoids have demonstrated potent differentiation and growth regulatory effects in normal, transformed, and hematopoietic progenitor cells. All-
retinoic acid (ATRA) is the paradigm of treatment in acute promyelocytic leukemia, an AML subtype. The majority of AML subtypes are, however, resistant to ATRA. Multiple synthetic retinoids such as ST1926 recently emerged as potent anticancer agents to overcome such resistance. Despite its lack of toxicity, ST1926 clinical development was restricted due to its limited bioavailability and rapid excretion. Here, we investigate the preclinical efficacy of ST1926 and polymer-stabilized ST1926 nanoparticles (ST1926-NP) in AML models. We show that sub-μmol/L concentrations of ST1926 potently and selectively inhibited the growth of ATRA-resistant AML cell lines and primary blasts. ST1926 induced-growth arrest was due to early DNA damage and massive apoptosis in AML cells. To enhance the drug's bioavailability, ST1926-NP were developed using Flash NanoPrecipitation, and displayed comparable anti-growth activities to the naked drug in AML cells. In a murine AML xenograft model, ST1926 and ST1926-NP significantly prolonged survival and reduced tumor burden. Strikingly,
ST1926-NP antitumor effects were achieved at four fold lower concentrations than the naked drug. These results highlight the promising use of ST1926 in AML therapy and encourage its further development.
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Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although targeted therapy in combination with chemotherapy in CRC prolongs the overall survival of ...patients with metastatic disease, acquired resistance and relapse hinder their clinical benefits. Moreover, patients with some specific genetic profile are unlikely to benefit from targeted therapy, suggesting the need for safe and effective treatment strategies. Retinoids, comprising of natural and synthetic analogs, are a class of chemical compounds that regulate cellular proliferation, differentiation, and cell death. Retinoids have been used in the clinic for several leukemias and solid tumors, either as single agents or in combination therapy. Furthermore, retinoids have shown potent chemotherapeutic and chemopreventive properties in different cancer models, including CRC. In this review, we summarize the major preclinical findings in CRC in which natural and synthetic retinoids showed promising antitumor activities and stress on the proposed mechanisms of action. Understanding of the retinoids’ antitumor mechanisms would provide insights to support and warrant their development in the management of CRC.
Despite recent advances in chemotherapy, aggressive and metastatic breast cancers remain refractory to targeted therapy and the development of novel drugs is urgently needed. Retinoids are crucial ...regulators of cellular proliferation, differentiation, and cell death, and have shown potent chemotherapeutic and chemopreventive properties. The major drawback of the use of all-trans retinoic acid (ATRA) in cancer therapy is disease relapse. Therefore, synthetic retinoids, specifically ST1926, have emerged as potent anticancer agents. Given the importance of the microenvironment in modulating the response of cancer cells to chemotherapeutic drugs, we investigated the antitumor activities of ST1926 in two-dimensional (2D) and different three-dimensional (3D) human breast cancer models and compared them with ATRA. We have shown that in 2D cell culture models, ATRA-resistant MCF-7 and MDA-MB-231 cells were sensitive to ST1926 at submicromolar concentrations that spared the 'normal-like' breast epithelial cells. ST1926 induced apoptosis and S-phase arrest, caused DNA damage, and downregulated the Wnt/β-catenin pathway in breast cancer cells in 2D and 3D cell culture models. ST1926-mediated growth inhibition was independent of the retinoid receptor-signaling pathway. Long-term treatments with low submicromolar ST1926 concentrations reduced the anchorage-independent growth and decreased the sphere-forming ability of breast cancer progenitor cells in the sphere formation assay. Furthermore, ST1926 potently induced cell death of breast cancer cells under 3D conditions and spared the lumen-forming ability of normal-like breast epithelial cells. In tested 3D models, ATRA had minimal effects on the growth of breast cancer cells compared with ST1926. In summary, our results highlight the therapeutic potential of ST1926 in breast cancer and warrant its further clinical development.
Abstract
Introduction: 5-fluorouracil (5-Fu) remains the standard chemotherapy for metastatic colorectal cancer (CRC), but drug resistance and unpredictable cardiotoxicity limit its effectiveness. ...The high recurrence rates and the common resistance are thought to be due to a population of self-renewing cancer stem cells (CSCs). The black seed extract Thymoquinone (TQ) is a promising anticancer molecule known to inhibit cancer cell growth and progression in numerous cancer systems both in vitro and in vivo. This project aims to investigate the effect and mechanism of action of TQ on colon cancer stem/progenitor cells using two isogenic HCT116 colon cancer cell lines that differ in their 5-Fu drug sensitivity.
Methods: Sphere-formation and propagation assays were used to assess the efficacy of TQ on targeting self-renewal capacity of colon CSCs enriched from the sensitive and resistant cell lines in 3D cultures over several generations in comparison to 2D monolayers. In addition, xenotransplantation experiments were used to assess for the tumor initiation of 2D vs. 3D cells.
Results: Our results of TQ efficacy in 2D cell culture system showed that it reduced the viability of both cell lines. Importantly, our 3D results showed that TQ inhibits HCT116 colonosphere growth at 10-fold lower concentrations than those required to inhibit the growth of 2D monolayer cells. Interestingly, the injection of 100 spheres derived from HCT116 sensitive cell line and not the 2D equivalent cell density into NOD-SCID immunocompromised mice resulted in tumor development, suggesting that spheres are rich in cells with stem-like properties.
Conclusion: In summary, our data suggests that TQ might be an effective treatment strategy and may prevent colorectal cancer recurrence by targeting CSCs.
Citation Format: Farah R. Ballout, Maamoun Fatfat, Rana Abdel-Samad, Nadine Darwiche, Regine Schneider-Stock, Wassim Abou-Kheir, Hala-Gali Muhtasib. Targeting colorectal cancer stem cells with the anticancer molecule thymoquinone abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 170.
The high recurrence rates of colorectal cancer have been associated with a small population of cancer stem cells (CSCs) that are resistant to the standard chemotherapeutic drug, 5-fluorouracil (5FU). ...Thymoquinone (TQ) has shown promising antitumor properties on numerous cancer systems both
in vitro
and
in vivo
; however, its effect on colorectal CSCs is poorly established. Here, we investigated TQ’s potential to target CSCs in a three-dimensional (3D) sphere-formation assay enriched for a population of colorectal cancer stem/progenitor cells. Our results showed a significant decrease in self-renewal potential of CSC populations enriched from 5FU-sensitive and resistant HCT116 cells at 10-fold lower concentrations when compared to 2D monolayers. TQ decreased the expression levels of colorectal stem cell markers CD44 and Epithelial Cell Adhesion Molecule EpCAM and proliferation marker Ki67 in colonospheres derived from both cell lines and reduced cellular migration and invasion. Further investigation revealed that TQ treatment led to increased TUNEL positivity and a dramatic increase in the amount of the DNA damage marker gamma H2AX particularly in 5FU-resistant colonospheres, suggesting that the diminished sphere forming ability in TQ-treated colonospheres is due to induction of DNA damage and apoptotic cell death. The intraperitoneal injection of TQ in mice inhibited tumor growth of spheres derived from 5FU-sensitive and 5FU-resistant HCT116 cells. Furthermore, TQ induced apoptosis and inhibited NF-κB and MEK signaling in mouse tumors. Altogether, our findings document TQ’s effect on colorectal cancer stem-like cells and provide insights into its underlying mechanism of action.
Abstract
Despite recent advances in breast cancer therapy, achieving complete remission in metastatic breast cancer patients remains a challenge. Retinoids are crucial regulators of cellular ...proliferation, differentiation, and cell death, and have shown potent chemotherapeutic and chemopreventive properties. The major drawback of the use of all-trans retinoic acid (ATRA) in cancer therapy is acquired resistance. Therefore, synthetic retinoids such as ST1926 emerged as potent anti-cancer agents. Here, we investigated the anti-tumor activities of ATRA, ST1926, and their combination treatments in 2D and 3D human breast cancer models and their targeting of breast cancer stem cells (CSCs)/progenitor cells. We have shown that in 2D culture models, MCF-7 and MDA-MB-231 cells are resistant to ATRA while being sensitive to ST1926 at sub-micromolar (μM) concentrations in an irreversible manner. Importantly, ST1926 had no effect on the ‘normal-like’ MCF-10A breast epithelial cells. ST1926 induced massive apoptosis in MCF-7 cells and it resulted in S-phase arrest and necrosis in the triple negative and metastatic MDA-MB-231 cells. Furthermore, ST1926 caused early DNA damage, increased the expression of the tumor suppressors p53 and p21, downregulated the Wnt/β-catenin pathway, and modulated the expression levels of the different retinoid receptors. Interestingly, combination treatments as low as 0.1 μM ST1926 and 0.5 μM ATRA synergistically inhibited the proliferation in 2D models of MCF-7 and MDA-MB-231 cells, independently of retinoid receptor signaling, while sparing the normal breast epithelial cells. Anchorage-independent growth of MCF-7 and MDA-MB-231 cells was examined using the soft agar colony formation assay where sub-μM concentrations of ST1926 or μM concentrations of ATRA were shown to reduce the size and the number of breast cancer colonies. ST1926 drastically induced cell death in 3D Matrigel ‘on-top’ assay cultures of breast cancer cells while the lumen of the normal-like breast epithelial cell line S1 was maintained. Finally, treatment with 0.01 μM ST1926 alone or 0.001 μM ST1926 in combination with 0.1 μM ATRA abrogated sphere formation and the self-renewal ability of breast CSCs in the 3D sphere formation assay. In summary, ST1926, ATRA, and their combination treatments were shown to display more potent anti-tumor properties in 3D versus 2D human breast cancer models. Our results also demonstrate the therapeutic potential of ST1926 in sensitizing breast cancer cells to ATRA and in targeting the population of breast CSCs. As 3D culture models are more representative of the tumor microenvironment and serve as valid tools in drug discovery, our results highlight the promising use of ATRA/ST1926 combinations in metastatic and triple negative breast cancers.
Citation Format: Patrick Aouad, Melody Saikali, Rana Abdel-Samad, Leeanna El–Houjeiri, Claudio Pisano, Rabih Talhouk, Nadine Darwiche. Combination treatments with retinoic acid and the synthetic retinoid ST1926 in 2D and 3D breast cancer models overcome retinoic acid resistance and eradicate breast cancer stem/progenitor cells. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1189.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL ...carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1–positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL.
•The synthetic retinoid ST1926 induces apoptosis of ATL cells and prolongs survival of ATL mice.•At the molecular level, ST1926 causes early DNA damage, upregulates p53, and downregulates Tax expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Primary effusion lymphoma (PEL) is a rare B-cell neoplasm, associated with Kaposi sarcoma-associated herpes virus/human herpes virus-8 (KSHV/HHV-8), arising as malignant effusions in body cavities. ...PEL cells do not harbor conventional genetic cancer mutations; however, their oncogenesis is mainly attributed to HHV-8 latent genes. Treatment strategies are inefficient resulting in poor prognosis of PEL patients, stressing the need for new effective therapy. ST1926 is a synthetic retinoid with favorable antitumor properties and no cross-resistance with the natural retinoid, all-trans retinoic acid. ST1926 has shown potent apoptotic activities on a variety of solid tumors and hematologic malignancies in in vitro and in vivo models. In the present study we elucidated the antitumor activities and underlying molecular mechanism of ST1926 using in vitro, ex vivo, and in vivo PEL preclinical models. ST1926, at sub‑micromolar concentrations, displayed potent antiproliferative effects on PEL cell lines and malignant ascites. Furthermore, ST1926 treatment of PEL cells and ascites resulted in their accumulation in the sub-G1 region, S phase cell cycle arrest, early DNA damage, PARP cleavage and p53 activation including the upregulation of its target genes p21 and Bax. However, ST1926 did not significantly modulate HHV-8 latent viral transcripts. Importantly, ST1926 delayed formation of ascites and enhanced survival of PEL mice. These results highlight the therapeutic potential of ST1926 in combination with drugs that target HHV-8 in PEL patients.
Abstract
Acute myeloid leukemia (AML) represents one of the most complex types of leukemia. It is a clinically and genetically heterogeneous disorder of hematopoietic progenitor cells, which have ...lost their ability to differentiate normally. Retinoids regulate vital biological processes including development, differentiation, proliferation, and cell death of hematopoietic progenitor cells. The natural retinoid all-trans retinoic acid (ATRA) became the paradigm for the treatment of acute promyelocytic leukemia (APL), an AML subtype. However, in non-APL AML patients, ATRA is possibly only effective in patients with Nucleophosmin-1 mutations without FMS-like tyrosine kinase 3 internal tandem duplication (FLT-3 ITD). Therefore, synthetic retinoids, specifically the adamantyl ST1926, emerged as potential alternatives. However, despite its lack of toxicity, ST1926 development in clinic was limited due to its rapid glucuroconjugation resulting in low plasma concentrations. Nanomedicine enables more efficient drug delivery and bioavailability. Here, we investigate the pre-clinical efficacy of ST1926 and polymer stabilized ST1926 nanoparticles in AML in vitro and in vivo models. We show that ST1926, at low sub-µM concentrations, potently inhibited the growth of human non-APL ATRA-resistant AML cell lines and AML patient cells while sparing resting and activated normal leukocytes at ten- to hundred-fold higher concentrations. ST1926 induced early DNA damage and massive apoptosis in all tested AML cell lines. To optimize the drug’s bioavailability burden, polymer stabilized ST1926 nanoparticles were developed using Flash NanoPrecipitation, and were shown to display comparable anti-growth activities to the naked drug in vitro. In murine AML xenograft model, ST1926 and ST1926 nanoparticles significantly prolonged survival. Strikingly, ST1926 encapsulated in nanoparticles extended survival in AML xenografted mice at four-fold lower concentrations than the naked drug. These results highlight the promise of ST1926 in AML therapy and warrant further clinical development of this adamantly retinoid.
Citation Format: Leeanna El-Houjeiri, Walid Saad, Berthe Hayar, Patrick Aouad, Nadim Tawil, Rana Abdel-Samad, Claudio Pisano, Ali Bazarbachi, Hiba El Hajj, Nadine Darwiche. Encapsulation of the atypical retinoid ST1926 in nanoparticles prolongs the survival of acute myeloid leukemia xenografted mice at multiple folds lower concentrations than the naked drug abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5140. doi:10.1158/1538-7445.AM2017-5140
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