Calcitriol enhances gemcitabine antitumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system

Yu, Weidong; Ma, Yingyu; Flynn, Geraldine; Muindi, Josephia R.; Kong, Rui-Xian; Trump, Donald L.; Johnson, Candace S.

doi:10.4161/cc.9.15.12381

Cited by 54 publications

(47 citation statements)

References 25 publications

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“…[2][3][4] At the cellular level, 1,25(OH) 2 D 3 modulates proliferation, differentiation, survival, metabolism and physiology and potentiates the antitumoral activity of certain chemotherapeutic agents in a celltype-and -context-dependent manner. [5][6][7][8][9][10] According to the classical model of action, 1,25(OH) 2 D 3 binds to and activates a transcription factor of the nuclear receptor superfamily, the vitamin D receptor (VDR), and modulates the transcription rate of its target genes. 11 1,25(OH) 2 D 3 is a major regulator of gene expression in higher organisms, as VDR is expressed in at least 38 human cell types.…”

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confidence: 99%

Vitamin D has wide regulatory effects on histone demethylase genes

et al. 2012

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confidence: 99%

Vitamin D has wide regulatory effects on histone demethylase genes

et al. 2012

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“…It is known that calcitriol has antiproliferative activity through different mechanisms such as cell cycle arrest and apoptosis (38)(39)(40)(41). Additionally, calcitriol can enhance anti-cancer activity of anti-cancer drugs including gemcitabine (42) and paclitaxel (43) both in vitro and in vivo.…”

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confidence: 99%

Calcitriol Reverses Induced Expression of Efflux Proteins and Potentiates Cytotoxic Activity of Gemcitabine in Capan-2 Pancreatic Cancer Cells

Kohan¹,

Sani²,

Boroujerdi³

2017

J Pharm Pharm Sci

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ABSTRACT-Purpose. Efflux and influx proteins play a major role in chemo-resistance by affecting the net cellular uptake of anti-cancer drugs. Hence, alteration of the efflux and influx protein expression may result in variations of chemotherapeutics uptake and consequently cell death rate. The present study investigated the effects of pre-treatment of capan-2 pancreatic cancer cells with calcitriol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or silibinin on the induction of three major efflux proteins and the main gemcitabine influx protein. The influence of the pre-treatments on the net cellular uptake of gemcitabine, total ATPase activity, and cell death rate were also evaluated. Methods. Capan-2 pancreatic cancer cells were pre-treated for 24 h with calcitriol, BHT, BHA, or silibinin, followed by gemcitabine treatment. The concentration of gemcitabine was quantified using ultra-performance liquid chromatography (UPLC). Real-time polymerase chain reaction (RT-PCR) was utilized in order to investigate the expression of the mRNAs. The expression of the proteins was assessed using western blotting. Measurement of the ATPase activity was conducted utilizing a colorimetric method and viability of the cells was determined using a luminescent cell viability assay. Results. Protein expression studies showed that BHT, silibinin, and BHA increased expression of the efflux proteins and decreased the overall uptake of gemcitabine, whereas calcitriol significantly inhibited expression of the efflux proteins and increased gemcitabine uptake. Expression of specific mRNAs correlated reasonably well with the levels of corresponding proteins. Additionally, the expression of efflux proteins and ATPase activity were well correlated, signifying that the induced efflux proteins are functionally active. Moreover, pre-treatment with calcitriol resulted in a significant increase in cell death with gemcitabine treatment, whereas, BHA significantly reduced the cell death rate. On the other hand, pre-treatment with BHT and silibinin had no significant effect on the cell death rate. Conclusions. Pre-treatment of the pancreatic cancer cells with calcitriol significantly increased gemcitabine cellular uptake and consequently decreased cell viability after treatment with gemcitabine, whereas BHA significantly reduced gemcitabine uptake and decreased cell death rate, which were at least partially attributed to the alteration of expression of efflux and influx proteins.

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“…26,27 Mechanisms of GMT-mediated apoptosis have been investigated in several cancers. [28][29][30][31] GMT has been increasingly used to treat hepatobiliary cancers because of its reasonable efficacy for treating pancreatic cancer. 32 Low dose of GMT is preferred to avoid severe toxicity, especially pulmonary toxicity.…”

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“…6,[20][21][22][23][24][25] Based on previously published data, TMX and GMT appear to induce apoptosis via distinct mechanisms. 11,13,[28][29][30][31] Therefore, we evaluated the efficacy of combination therapy with TMX and GMT on human cholangiocarcinoma tumorigenesis in a mouse xenograft model and investigated the responsible molecular mechanisms. We have found that TMX and GMT induce apoptosis and inhibit cholangiocarcinoma tumorigenesis.…”

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Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis

Yuan

Turk

et al. 2011

Laboratory Investigation

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Cholangiocarcinoma is a highly malignant tumor with limited therapeutic options. We have previously reported that tamoxifen (TMX) induces apoptosis of cholangiocarcinoma cells and reduces cholangiocarcinoma tumorigenesis in mice.In the present studies, we determined the effect of combination therapy of TMX and gemcitabine (GMT), another chemotherapeutical reagent for many cancers, on cholangiocarcinoma tumorigenesis and investigated the responsible mechanisms. GMT inhibited cell growth and induced apoptosis of cholangiocarcinoma cells in a concentrationdependent manner. TMX enhanced GMT-induced apoptosis of cholangiocarcinoma cells. Consistently, GMT (15 mg/kg) inhibited cholangiocarcinoma tumorigenesis in nude mice by 50%. TMX (15 mg/kg) enhanced the inhibitory effect of GMT on tumorigenesis by 33%. The inhibition of tumor growth correlated with enhanced apoptosis in tumor tissues. To elucidate the mechanisms underlying the additive effects of TMX on GMT-induced apoptosis, we determined the activation of caspases in cholangiocarcinoma cells exposed to GMT, TMX, or both. Activation of caspases 9 and 3, as well as cytochrome c release to the cytosol, was demonstrated in cells exposed to both reagents. In contrast, TMX activated caspase 2, whereas GMT had no effect. Inhibition of caspase 2 activation decreased TMX-, but not GMT-, induced activation of caspase 3 and apoptosis of cholangiocarcinoma cells. Similarly, activation of caspase 2 was found in tumors from TMX-treated mice, but not GMT-treated mice. Therefore, the enhanced effect of TMX on GMT-induced cholangiocarcinoma cell death is partially mediated by activation of caspase 2. TMX and GMT both induce apoptosis and inhibit cholangiocarcinoma tumorigenesis, which may be attributed to the activation of distinct apoptosis signals by TMX and GMT. Our studies provide in vivo evidence and molecular insight to support the use of TMX and GMT in combination as an effective therapy for cholangiocarcinoma.

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Calcitriol enhances gemcitabine antitumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system

Abstract: (2010) Calcitriol enhances gemcitabine antitumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system, Cell Cycle, 9:15, 3094-3101,

Cited by 54 publications

References 25 publications

Vitamin D has wide regulatory effects on histone demethylase genes

Vitamin D has wide regulatory effects on histone demethylase genes

Calcitriol Reverses Induced Expression of Efflux Proteins and Potentiates Cytotoxic Activity of Gemcitabine in Capan-2 Pancreatic Cancer Cells

Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis

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