Targeting sine oculis homeoprotein 1 (SIX1): A review of oncogenic roles and potential natural product therapeutics.

Sine oculis homeoprotein 1 (SIX1), a prominent representative of the homeodomain transcription factors within the SIX family, has attracted significant interest owing to its role in tumorigenesis, cancer progression, and prognostic assessments. Initially recognized for its pivotal role in embryonic development, SIX1 has emerged as a resurgent factor across a diverse set of mammalian cancers. Over the past two decades, numerous investigations have emphasized SIX1's dual significance as a developmental regulator and central player in oncogenic processes.

Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice.

The androgen receptor (AR) is the main driver in the development of castration-resistant prostate cancer, where the emergence of AR splice variants leads to treatment-resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs.

Racial differences in serum chemokines in prostate cancer patients.

Background: This study aimed to understand the differential levels of inflammatory chemokines in association with higher prostate cancer incidence and mortality in African American (AA) men than in Caucasians (CA).

Methods: The authors used a chemokine assay to simultaneously measure 40 chemokines and cytokines levels in the serum of preoperative prostate cancer patients and healthy controls of AA and CA races. Selected chemokines (CXCL2, CXCL5, and CCL23) serum level was validated in 211 serum samples from prostate cancer patients and healthy controls.

DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent Pathway.

Epigenetic alterations such as DNA methylation and histone modifications are implicated in repressing several tumor suppressor genes in prostate cancer progression. In this study, we determined the anti-prostate cancer effect of a small molecule drug guadecitabine (gDEC) that inhibits/depletes the DNA methylation writer DNA methyltransferase 1 (DNMT1). gDEC inhibited prostate cancer cell growth and proliferation in vitro without activating the apoptotic cascade.

CCL23 in Balancing the Act of Endoplasmic Reticulum Stress and Antitumor Immunity in Hepatocellular Carcinoma.

Endoplasmic reticulum (ER) stress is a cellular process in response to stress stimuli in protecting functional activities. However, sustained hyperactive ER stress influences tumor growth and development. Hepatocytes are enriched with ER and highly susceptible to ER perturbations and stress, which contribute to immunosuppression and the development of aggressive and drug-resistant hepatocellular carcinoma (HCC).

RSK1 vs. RSK2 Inhibitory Activity of the Marine β-Carboline Alkaloid Manzamine A: A Biochemical, Cervical Cancer Protein Expression, and Computational Study.

Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A's (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2.

A Perspective on Modulating Antitumor Immunity in Targeting Prostate Cancer.

Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a bioactive ingredient of , has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements.

Circulatory MIC-1 as a Determinant of Prostate Cancer Racial Disparity.

In this study, we investigated the potential of MIC-1 (macrophage inhibitory cytokine-1) on the severity of prostate cancer between African American men and Caucasians. Differences between the races were examined using Mann-Whitney tests for continuous variables and Fisher's exact tests for categorical variables. Pearson's correlation coefficient was used to identify associations between continuous measures across all samples and within each race.

The Marine Natural Product Manzamine A Inhibits Cervical Cancer by Targeting the SIX1 Protein.

Natural products remain an important source of drug leads covering unique chemical space and providing significant therapeutic value for the control of cancer and infectious diseases resistant to current drugs. Here, we determined the antiproliferative activity of a natural product manzamine A () from an Indo-Pacific sponge following various in vitro cellular assays targeting cervical cancer (C33A, HeLa, SiHa, and CaSki). Our data demonstrated the antiproliferative effects of at relatively low and non-cytotoxic concentrations (up to 4 μM).

Inflammasomes: Emerging Central Players in Cancer Immunology and Immunotherapy.

Inflammation has an established role in cancer development and progression and is a key player in regulating the entry and exit of immune cells in the tumor microenvironment, mounting a significant impact on anti-tumor immunity. Recent studies have shed light on the role of inflammasomes in the regulation of inflammation with a focus on the subsequent effects on the immunobiology of tumors. To generate strong anti-tumor immunity, cross-talk between innate, and adaptive immune cells is necessary.

Withaferin A Associated Differential Regulation of Inflammatory Cytokines.

A role of inflammation-associated cytokines/chemokines has been implicated in a wide variety of human diseases. Here, we investigated the regulation of inflammatory cytokines released by monocyte-derived THP-1 cells following treatment with the dietary agent withaferin A (WFA). Membrane-based cytokine array profiling of the culture supernatant from adenosine triphosphate-stimulated WFA-treated THP-1 cells showed differential regulation of multiple cytokines/chemokines.

Formulation of the bivalent prostate cancer vaccine with surgifoam elicits antigen-specific effector T cells in PSA-transgenic mice.

We previously developed and characterized an adenoviral-based prostate cancer vaccine for simultaneous targeting of prostate-specific antigen (PSA) and prostate stem cell antigen (PSCA). We also demonstrated that immunization of mice with the bivalent vaccine (Ad-PSA+PSCA) inhibited the growth of established prostate tumors. However, there are multiple challenges hindering the success of immunological therapies in the clinic.

Expression analysis of inflammasome sensors and implication of NLRP12 inflammasome in prostate cancer.

Inflammasomes are multi-proteins complex regulating inflammation-associated signaling. While inflammation plays a critical role in cancer cell growth, studies remain uncharacterized on the role of inflammasomes in prostate cancer. Using Gene Expression Omnibus (GEO) public datasets, we screened the expression profiles of inflammasome sensors NLRP3, NLRC4, NLRP6, NRLP12, and AIM2 in prostate tumor tissues, and verified their mRNA level in a panel of prostate cancer cell lines.

From Inflammation to Prostate Cancer: The Role of Inflammasomes.

Inflammation-associated studies entice specific attention due to inflammation's role in multiple stages of prostate cancer development. However, mechanistic regulation of inflammation inciting prostate cancer remains largely uncharacterized. A focused class of inflammatory regulators known as inflammasomes has recently gained attention in cancer development.

Combination immunotherapy with prostate GVAX and ipilimumab: safety and toxicity.

Evaluation of: van den Eertwegh AJ, Versluis J, van den Berg HP et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a Phase 1 dose-escalation trial. Lancet Oncol.

Inflammation-associated regulation of the macrophage inhibitory cytokine (MIC-1) gene in prostate cancer.

Macrophage inhibitory cytokine-1 (MIC-1), also known as prostate-derived factor (PDF), is a molecule of the TGF-β superfamily and has been associated with the progression of various types of diseases including prostate cancer. Initially identified from activated macrophages, the MIC-1 gene may provide a potential link between inflammation and prostate cancer. In this context, we performed MIC-1 expression analysis using mouse prostate tissues to determine whether there was any correlation with age and inflammation.

Cancer immunotherapy: a paradigm shift for prostate cancer treatment.

Prostate cancer remains a significant health problem for men in the Western world. Although treatment modalities are available, these do not confer long-term benefit and are accompanied by deleterious side effects. Immunotherapy represents a valuable alternative to conventional treatments by inducing tumour-specific immune responses that control the growth of cancer cells.

Dual antigen target-based immunotherapy for prostate cancer eliminates the growth of established tumors in mice.

Aims: We have previously shown that immunization with an adenovirus vector carrying an individual antigen induces antigen-specific CD8 T cells actively engaged in the destruction of tumor cells expressing the cognate antigen. In order to expand the range of antitumor responses beyond an individual antigen, we designed a recombinant adenovirus type 5 (rAd5) carrying a fusion construct of two full-length antigens. We used this adenovirus vector to test the concept that multiantigenic effector T cells could be generated simultaneously following a single immunization.

CpG oligonucleotide as an adjuvant for the treatment of prostate cancer.

The use of an adenovirus transduced to express a prostate cancer antigen (PSA) as a vaccine for the treatment of prostate cancer has been shown to be active in the destruction of antigen-expressing prostate tumor cells in a pre-clinical model, using Balb/C or PSA transgenic mice. The destruction of PSA-secreting mouse prostate tumors was observed in Ad/PSA immunized mice in a prophylaxis study with 70% of the mice surviving long term tumor free. This successful immunotherapy was not observed in therapeutic studies in which tumors were established before vaccination and the development of anti-PSA immune response was not as easily generated in PSA transgenic mice.

Aqueous extract of Rhodiola imbricata rhizome stimulates Toll-like receptor 4, granzyme-B and Th1 cytokines in vitro.

Rhodiola imbricata is a medicinal plant, native to mountainous regions of Asia, parts of Europe, and the Arctic. Traditionally it is recommended to help combat fatigue and restore energy. It exhibits anti-stress, anti-cancer, and immunostimulatory activities.

Macrophage inhibitory cytokine-1: possible bridge molecule of inflammation and prostate cancer.

There is emerging evidence that inflammation may lead to prostate cancer development. Although inflammation is an essential response to injury or infection, chronic inflammation is harmful and causes tissue damage. Increasing evidence suggests that inflammation leads to the development of epithelial cancers; however, studies on inflammation-targeted genes that might contribute to the development of cancer are at the beginning stage.

Paradoxical enhancement of CD8 T cell-dependent anti-tumor protection despite reduced CD8 T cell responses with addition of a TLR9 agonist to a tumor vaccine.

Generation of antigen-specific CD8+ T cell responses is considered optimal for an effective immunotherapy against cancer. In this study, we provide a proof of principle that in vitro observed diminished CD8+ T cell response provided a strong in vivo tumor protection. Immunization with an adenovirus vaccine containing ovalbumin (OVA) gene (Ad5-OVA) strongly induces antigen-specific CD8+ T cell responses measured in vitro using various immunological assays.

Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells.

Background: The expression of prostate-derived factor (PDF) is significantly elevated in human prostate tumors. We investigate the functional role and signaling of PDF in androgen receptor (AR)-positive human prostate cancer cells.

Methods: Transient or stable expression of PDF by cDNA transfection, antisense-mediated gene silencing, media conditioned by PDF-elevated cells, and antibody (Ab) neutralization were employed.