The UCA1/miR-204/Sirt1 axis modulates docetaxel sensitivity of prostate cancer cells

Abstract

Purpose

In this study, we firstly investigated the regulative effect of miR-204 on Sirt1 expression in prostate cancer cells. Then, we examined whether miR-204 downregulation in the cells is a result of UCA1 upregulation. In addition, the regulative effect of UCA1/miR-204/Sirt1 axis on docetaxel sensitivity of prostate cancer cells was studied.

Methods

QRT-PCR was performed to detect UCA1, miR-204 and Sirt1 mRNA expression. Western blot assay was performed to assess Sirt1, P-gp and caspase-3 expression. The regulative effect of UCA1/miR-204/Sirt1 axis on docetaxel sensitivity of prostate cancer cells was examined by measurement of docetaxel IC50, dictation of cleaved caspase-3 and flow cytometric analysis of cell apoptosis.

Results

MiR-204 negatively modulated Sirt1 expression in prostate cancer cells. UCA1 upregulation directly resulted in decreased miR-204 expression. UCA1 overexpression resulted in increased Sirt1 expression in PNT2 cells, while knockdown of endogenous UCA1 led to decreased Sirt1 in LNCaP and 22RV1 cells. UCA1 siRNA, Sirt1 siRNA and miR-204 mimics could enhance docetaxel-induced activation of caspase-3 and cell apoptosis in 22RV1/DR cells.

Conclusions

There is a UCA1/miR-204/Sirt1 axis in LNCaP and 22RV1 cells. The UCA1/miR-204/Sirt1 axis plays an important role in modulating in vitro docetaxel sensitivity of the prostate cancer cells.

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Randomized phase 1 crossover study assessing the bioequivalence of capsule and tablet formulations of dovitinib (TKI258) in patients with advanced solid tumors

Abstract

Purpose

A capsule formulation of the tyrosine kinase inhibitor dovitinib (TKI258) was recently studied in a phase 3 renal cell carcinoma trial; however, tablets are the planned commercial formulation. Therefore, this randomized 2-way crossover study evaluated the bioequivalence of dovitinib tablet and capsule formulations in pretreated patients with advanced solid tumors, excluding breast cancer.

Methods

In this 2-part study, eligible patients received dovitinib 500 mg once daily on a 5-days-on/2-days-off schedule. During the 2-period bioequivalence phase, patients received their initial formulation (capsule or tablet) for 3 weeks before being switched to the alternative formulation in the second period. Patients could continue to receive dovitinib capsules on the same dosing schedule during the post-bioequivalence phase.

Results

A total of 173 patients were enrolled into the bioequivalence phase of the study (capsule → tablet, n = 88; tablet → capsule, n = 85), and 69 patients had evaluable pharmacokinetics (PK) for both periods. PK analyses showed similar exposure and PK profiles for the dovitinib capsule and tablet formulations and supported bioequivalence [geometric mean ratios: AUC_last, 0.95 (90 % CI 0.88–1.01); C _max, 0.98 (90 % CI 0.91–1.05)]. The most common adverse events, suspected to be study drug related, included diarrhea (60 %), nausea (53 %), fatigue (45 %), and vomiting (43 %). Of 168 patients evaluable for response, 1 achieved a partial response, and stable disease was observed in 32 % of patients.

Conclusions

Dovitinib capsules and tablets were bioequivalent, with a safety profile similar to that observed in other dovitinib studies of patients with heavily pretreated advanced solid tumors.

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Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice

Abstract

An immunotherapeutic strategy is discussed supporting anti-tumor activity toward malignancies overexpressing ganglioside D3. GD3 can be targeted by NKT cells when derived moieties are presented in the context of CD1d. NKT cells can support anti-tumor responses by secreting inflammatory cytokines and through cytotoxicity toward CD1d⁺GD3⁺ tumors. To overexpress GD3, we generated expression vector DNA and an adenoviral vector encoding the enzyme responsible for generating GD3 from its ubiquitous precursor GM3. We show that DNA encoding α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (SIAT8) introduced by gene gun vaccination in vivo leads to overexpression of GD3 and delays tumor growth. Delayed tumor growth is dependent on CD1d expression by host immune cells, as shown in experiments engaging CD1d knockout mice. A trend toward greater NKT cell populations among tumor-infiltrating lymphocytes is associated with SIAT8 vaccination. A single adenoviral vaccination introduces anti-tumor activity similarly to repeated vaccination with naked DNA. Here, greater NKT tumor infiltrates were accompanied by marked overexpression of IL-17 in the tumor, later switching to IL-4. Our results suggest that a single intramuscular adenoviral vaccination introduces overexpression of GD3 by antigen-presenting cells at the injection site, recruiting NKT cells that provide an inflammatory anti-tumor environment. We propose adenoviral SIAT8 (AdV-SIAT8) can slow the growth of GD3 expressing tumors in patients.

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Status of oncologic specialties: global survey of physicians treating cancer

Abstract

Background

In the United States, medical oncologists play a central role in the management of systemic therapy for cancer patients. Medical oncology as a specialty is not as established in Japan and several other European nations according to recent surveys, and little is known about this specialty in developing nations. We aimed to identify global differences in the roles of physicians treating cancer; specifically, how the management of advanced disease differs among nations.

Methods

In March 2016, a self-administered internet survey was conducted with degreed physicians who prescribed systemic agents for adult cancer treatment within the past 5 years. Physicians were identified from the American Society of Clinical Oncology active member online directory.

Results

Among 3907 members in 55 nations, 376 (9.6%) responded to the survey. The 310 respondents who provided an answer to the recognition of medical oncology were dominated by male MDs that have practiced for more than 5 years at academic centers, and ~60% were medical oncologists. A majority of the respondents in all four regions reported that medical oncology was established in their corresponding nations. However, there are several outlying nations where oncologic specialties play a minimal role in the management of systemic therapy.

Conclusion

Despite general recognition of medical oncology, the role is not globally established as the primary point of care for delivery of systemic therapy. Nations lacking this specialty should be assisted by the international community to develop medical oncology.

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Capsaicin reactivates hMOF in gastric cancer cells and induces cell growth inhibition

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Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy

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Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice

Abstract

An immunotherapeutic strategy is discussed supporting anti-tumor activity toward malignancies overexpressing ganglioside D3. GD3 can be targeted by NKT cells when derived moieties are presented in the context of CD1d. NKT cells can support anti-tumor responses by secreting inflammatory cytokines and through cytotoxicity toward CD1d⁺GD3⁺ tumors. To overexpress GD3, we generated expression vector DNA and an adenoviral vector encoding the enzyme responsible for generating GD3 from its ubiquitous precursor GM3. We show that DNA encoding α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (SIAT8) introduced by gene gun vaccination in vivo leads to overexpression of GD3 and delays tumor growth. Delayed tumor growth is dependent on CD1d expression by host immune cells, as shown in experiments engaging CD1d knockout mice. A trend toward greater NKT cell populations among tumor-infiltrating lymphocytes is associated with SIAT8 vaccination. A single adenoviral vaccination introduces anti-tumor activity similarly to repeated vaccination with naked DNA. Here, greater NKT tumor infiltrates were accompanied by marked overexpression of IL-17 in the tumor, later switching to IL-4. Our results suggest that a single intramuscular adenoviral vaccination introduces overexpression of GD3 by antigen-presenting cells at the injection site, recruiting NKT cells that provide an inflammatory anti-tumor environment. We propose adenoviral SIAT8 (AdV-SIAT8) can slow the growth of GD3 expressing tumors in patients.

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