Design, synthesis and SAR study of 3rd-generation taxoids bearing 3-CH, 3-CFO and 3-CHFO groups at the C2-benzoate position.

It has been shown that inclusion of CFO and CHFO groups to drug candidates often improve their pharmacological properties, especially metabolic stability, membrane permeability and PK profile. Moreover, the unique non-spherical structure of the OCHF group can provide interesting and beneficial characteristics. Accordingly, new 3rd-generation taxoids, bearing 3-OCF or 3-OCFH (and 3-CH for comparison) at the C2 benzoate moiety, were synthesized and their potencies against drug-sensitive and drug-resistant cancer cell lines examined.

Biodistribution and Pharmacokinetic Evaluations of a Novel Taxoid DHA-SBT-1214 in an Oil-in-Water Nanoemulsion Formulation in Naïve and Tumor-Bearing Mice.

Purpose: The main purpose of this study was to formulate an oil-in-water nanoemulsion of a next generation taxoid DHA-SBT-1214 and evaluate its biodistribution and pharmacokinetics.

Methods: DHA-SBT-1214 was encapsulated in a fish oil containing nanoemulsion using a high pressure homogenization method. Following morphological characterization of the nanoemulsions, qualitative and quantitative biodistribution was evaluated in naïve and cancer stem cell-enriched PPT-2 human prostate tumor bearing mice.

Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth.

The main aim of this study was to evaluate the therapeutic efficacy of an oil-in-water nanoemulsion formulation encapsulating DHA-SBT-1214, a novel omega-3 fatty acid conjugated taxoid prodrug, against prostate cancer stem cells. Nanoemulsions of DHA-SBT-1214 (NE-DHA-SBT-1214) were prepared and characterized. In vitro delivery efficiency and cytotoxicity of NE-DHA-SBT-1214 was compared with solution formulation in PPT2 cells.

Establishment of highly tumorigenic human colorectal cancer cell line (CR4) with properties of putative cancer stem cells.

Background: Colorectal cancer (CRC) has the third highest mortality rates among the US population. According to the most recent concept of carcinogenesis, human tumors are organized hierarchically, and the top of it is occupied by malignant stem cells (cancer stem cells, CSCs, or cancer-initiating cells, CICs), which possess unlimited self-renewal and tumor-initiating capacities and high resistance to conventional therapies. To reflect the complexity and diversity of human tumors and to provide clinically and physiologically relevant cancer models, large banks of characterized patient-derived low-passage cell lines, and especially CIC-enriched cell lines, are urgently needed.

Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24.

Background: Prostate cancer is the second leading cause of cancer death among men. Multiple evidence suggests that a population of tumor-initiating, or cancer stem cells (CSCs) is responsible for cancer development and exceptional drug resistance, representing a highly important therapeutic target. The present study evaluated CSC-specific alterations induced by new-generation taxoid SBT-1214 and a novel polyenolic zinc-binding curcuminoid, CMC2.

Colon cancer stem cells--from basic to clinical application.

Based on cancer stem cell (CSC) concept of carcinogenesis, tumors represent complex heterogeneous organ-like systems with a hierarchical cellular organization, and only minority phenotypic subpopulations with stem-like properties possess a dual ability to self-renew indefinitely and produce all the heterogeneous cell phenotypes comprising the bulk tumor cells. Large experimental and clinical data indicate that conventional anti-cancer therapies cannot eradicate CSCs, and moreover, they usually increase their number leading to cancer recurrence and further drug resistance. In this review, several current controversies in the CSC field and recent studies, which help to shed light on their origin, are discussed.

New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells.

Background: Growing evidence suggests that the majority of tumors are organized hierarchically, comprising a population of tumor-initiating, or cancer stem cells (CSCs) responsible for tumor development, maintenance and resistance to drugs. Previously we have shown that the CD133high/CD44high fraction of colon cancer cells is different from their bulk counterparts at the functional, morphological and genomic levels. In contrast to the majority of colon cancer cells expressing moderate levels of CD133, CD44 and CD166, cells with a high combined expression of CD133 and CD44 possessed several characteristic stem cell features, including profound self-renewal capacity in vivo and in vitro, and the ability to give rise to different cell phenotypes.

Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells.

Background: Translational control mediated by non-coding microRNAs (miRNAs) plays a key role in the mechanism of cellular resistance to anti-cancer drug treatment. Dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS, TS) are two of the most important targets for antifolate- and fluoropyrimidine-based chemotherapies in the past 50 years. In this study, we investigated the roles of miR-215 in the chemoresistance to DHFR inhibitor methotrexate (MTX) and TS inhibitor Tomudex (TDX).

Phenotypic subpopulations of metastatic colon cancer stem cells: genomic analysis.

Background: Human cancer is characterized by high heterogeneity in gene expression, varieties of differentiation phenotypes and tumor-host interrelations. Growing evidence suggests that tumor-initiating, or cancer stem cells (CSCs), may also represent a heterogeneous population. The present study was undertaken to isolate and characterize the different phenotypic subpopulations of metastatic colon cancer and to develop a working colon CSC model for obtaining highly tumorigenic and clonogenic cells in sufficient numbers.

Genomic analysis of prostate cancer stem cells isolated from a highly metastatic cell line.

Background: Tumor-initiating or cancer stem cells (CSCs) were recently isolated from all major human cancers, including prostate cancer. However, the extreme heterogeneity of tumor cells in terms of biological behavior and gene expression patterns and difficulties isolating a pure population of CSCs from tumor tissues significantly impede a comparative analysis of CSCs.

Materials And Methods: Different phenotypic populations were isolated from a metastatic derivative of PC-3 cell line, PC3-MM2, and tested for their ability to form tumors in NOD/SCID mice and floating spheroids in 3D culture systems.

Clinical significance of telomerase activity in peritoneal disseminated cells: gastrointestinal cancers.

Early detection and accurate staging of gastrointestinal (GI) cancers are difficult. The aim of this study was to evaluate whether telomerase activity (TA) in exfoliated/disseminated epithelial cells could be used as a reliable marker for GI cancers. TA was evaluated with the real-time RTQ-TRAP in immunomagnetically sorted peritoneal epithelial cells from 60 patients undergoing surgical treatment.

Highly sensitive revealing of PCR products with capillary electrophoresis based on single photon detection.

Post-PCR fragment analysis was conducted using our single photon detection-based DNA sequencing instrument in order to substantially enhance the detection of nucleic biomarkers. Telomerase Repeat Amplification Protocol assay was used as a model for real-time PCR-based amplification and detection of DNA. Using TRAPeze XL kit, telomerase-extended DNA fragments were obtained in extracts of serial 10-fold dilutions of telomerase-positive cells, then amplified and detected during 40-cycle real-time PCR.

Noninvasive detection of prostate cancer by quantitative analysis of telomerase activity.

Purpose: Prostate cancer is the most common male malignancy and the second leading cause of male cancer death; therefore, there is urgent necessity for noninvasive assays for early detection of prostate cancer. Obtaining prostate tumor samples surgically is problematic because the malignancy is heterogeneous and multifocal and early-stage tumors are nonpalpable. In contrast, exfoliated cells represent the cancer status of the entire gland better due to the general tendency of cancer cells to exfoliate into biological fluids.