Colorectal carcinoma is a frequent cause of cancer-related death in the world for men and women. microRNAs are endogenous small noncoding RNAs that regulate gene expression negatively at post-transcriptional level. Here, we investigated the possible role of microRNAs in the development of multidrug resistance (MDR) in colorectal carcinoma cells. We analyzed microRNA (miRNA) expression levels between multidrug resistant colorectal carcinoma cell line HCT116/L-OHP and its parent cell line HCT116 using a miRNA microarray. miR-1915 had the lowest expression of miRNA in HCT116/L-OHP cells compared to its parental cells. Overexpression of Bcl-2 is generally associated with tumor drug resistance, meanwhile Bcl-2 is a predicted target of miR-1915. We found that elevated levels of miR-1915 in the mimics-transfected HCT116/L-OHP cells reduced Bcl-2 protein level and the luciferase activity of a Bcl-2 3'-untranslated region-based reporter, and also sensitized these cells to some anticancer drugs. Taken together, our findings suggest that miR-1915 could play a role in the development of MDR in colorectal carcinoma cells at least in part by modulation of apoptosis via targeting Bcl-2.
Arsenical drugs have achieved hallmark success in treating patients with acute promyelocytic leukemia, but expanding their clinical utility to solid tumors has proven difficult with the contradiction between the therapeutic efficacy and the systemic toxicity. Here, leveraging efforts from materials science, biocompatible PEGylated arsenene nanodots (AsNDs@PEG) with high monoelemental arsenic purity that can selectively and effectively treat solid tumors are synthesized. The intrinsic selective killing effect of AsNDs@PEG is closely related to high oxidative stress in tumor cells, which leads to an activated valence‐change of arsenic (from less toxic As0 to severely toxic oxidation states), followed by decreased superoxide dismutase activity and massive reactive oxygen species (ROS) production. These effects occur selectively within cancer cells, causing mitochondrial damage, cell‐cycle arrest, and DNA damage. Moreover, AsNDs@PEG when applied in a multi‐drug combination strategy with β‐elemene, a plant‐derived anticancer drug, achieves synergistic antitumor outcomes, and its newly discovered on‐demand photothermal properties facilitate the elimination of the tumors without recurrence, potentially further expanding its clinical utility. In line of the practicability for a large‐scale fabrication and negligible systemic toxicity of AsNDs@PEG (even at high doses and with repetitive administration), a new‐concept arsenical drug with high therapeutic efficacy for selective solid tumor therapy is provided.
Prussian blue nanoprobes are widely studied and applied in tumor photothermal therapy (PTT) and magnetic resonance imaging (MRI), due to their low toxicity and excellent in vivo performance. However, the sizes of hitherto reported Prussian blue nanoprobes are generally larger than 50 nm, which greatly influence cell phagocytosis, in vivo circulation, and biodistribution. In this work, a novel method of doping zinc ions is used to control the size of Prussian blue nanoprobes. Consequently, the performances of the nanoprobes in PTT and MRI are both significantly improved. The results show that the minimum size of Prussian blue nanoprobes achieved by doping 10% zinc ions (abbreviated as SPBZn(10%)) is 3.8 ± 0.90 nm, and the maximum specific absorption coefficient, photothermal conversion efficiency, and longitudinal relaxation rates are 1.78 L g−1 cm−1, 47.33%, and 18.40 mm−1 s−1, respectively. In addition, the SPBZn(10%) nanoprobes provide excellent PTT efficacy on 4T1 tumor cells (killing rate: 90.3%) and breast cancer model (tumor inhibition rate: 69.4%). Toxicological experiment results show that the SPBZn(n%) nanoprobes exhibit no obvious in vitro cytotoxicity and they can be used safely in mice at doses below 100 mg kg−1. Therefore, SPBZn(10%) nanoprobes can potentially be used for effective cancer theranostics.
Bortezomib (BTZ), a proteasome inhibitor, is the first proteasome inhibitor to be used in clinical practice. Here we investigated the mechanisms underlying acquired bortezomib resistance in hepatocellular carcinoma (HCC) cells. Using stepwise selection, we established two acquired bortezomib-resistant HCC cell lines, a bortezomib-resistant HepG2 cell line (HepG2/BTZ) and bortezomib-resistant HuH7 cell line (HuH7/BTZ). The 50% inhibitory concentration values of HepG2/BTZ and HuH7/BTZ were respectively 15- and 39-fold higher than those of parental cell lines. Sequence analysis of the bortezomib-binding pocket in the β5-subunit showed no mutation. However, bortezomib-resistant HCC cells had increased expression of β1 and β5 proteasome subunits. These alterations of proteasome expression were accompanied by a weak degree of proteasome inhibition in bortezomib-resistant cells than that in wild-type cells after bortezomib exposure. Furthermore, bortezomib-resistant HCC cells acquired resistance to apoptosis. Bortezomib up-regulated pro-apoptotic proteins of the Bcl-2 protein family, Bax and Noxa in wild-type HCC cells. However, in bortezomib-resistant HCC cells, resistance to apoptosis was accompanied by loss of the ability to stabilize and accumulate these proteins. Thus, increased expression and increased activity of proteasomes constitute an adaptive and auto regulatory feedback mechanism to allow cells to survive exposure bortezomib.
Cancer is a preeminent threat to the human race, causing millions of deaths each year on the Earth. Traditionally, natural compounds are deemed promising agents for cancer treatment. Cantharidin (CTD)—a terpenoid isolated from blister beetles—has been used extensively in traditional Chinese medicines for healing various maladies and cancer. CTD has been proven to be protein phosphatase 2A (PP2A) and heat shock transcription factor 1 (HSF-1) inhibitor, which can be potential targets for its anticancer activity. Albeit, it harbors some toxicities, its immense anticancer potential cannot be overlooked, as the cancer-specific delivery of CTD could help to rescue its lethal effects. Furthermore, several derivatives have been designed to weaken its toxicity. In light of extensive research, the antitumor activity of CTD is evident in both in vitro as well as in vivo cancer models. CTD has also proven efficacious in combination with chemotherapy and radiotherapy and it can also target some drug-resistant cancer cells. This mini-review endeavors to interpret and summarize recent information about CTD anticancer potential and underlying molecular mechanisms. The pertinent anticancer strength of CTD could be employed to develop an effective anticarcinogenic drug.
Arsenical Drugs
In article number 2102054, Aiguo Wu, Tian Xie, Wei Tao, and co‐workers reveal PEGylated arsenene nanodots (AsNDs@PEG) with high monoelemental arsenic purity and negligible systemic toxicity as a new‐concept arsenical drug. This AsNDs@PEG, when applied in a low‐dose combination strategy with β‐elemene, a plant‐derived anticancer drug, achieves synergistic therapeutic outcomes.
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