Current Cancer Drug Targets - Volume 20, Issue 2, 2020

Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, Larrea tridentata and is known to possess antioxidant, anticancer activities and is used in traditional medicine in North America and Mexico. However, its prolonged consumption leads to liver damage and kidney dysfunction. Despite its toxicity and side effects, there is little awareness to forbid its consumption and its use in the treatment of medical ailments has continued over the years. Several reports discuss its therapeutic efficiency and its medical applications have tremendously been on the rise to date. There has been a recent surge of interest in the chemical synthesis of NDGA derivatives for therapeutic applications. NDGA derivatives have been developed as better alternatives to NDGA. Although several NDGA derivatives have been chemically synthesized as evidenced by recent literature, there is a paucity of information on their therapeutic efficacies. This review is to highlight the medicinal applications of NDGA, its toxicity evaluations and discuss the chemical derivatives of NDGA synthesized and studied so far and suggest to continue research interests in the development of NDGA analogs for therapeutic applications. We suggest that NDGA derivatives should be investigated more in terms of chemical synthesis with preferred conformational structures and exploit their biological potentials with future insights to explore in this direction to design and develop structurally modified NDGA derivatives for potential pharmacological properties.

Background: MicroRNAs are endogenous, short, non-coding RNAs with the length as low as 20 to 25 nucleotides. These RNAs are able to negatively affect the gene expression at the post-transcriptional level. It has been demonstrated that microRNAs play a significant role in cell proliferation, cell migration, cell death, cell differentiation, infection, immune response, and metabolism. Besides, the dysfunction of microRNAs has been observed in a variety of cancers. So, modulation of microRNAs is of interest in the treatment of disorders. Objective: The aim of the current review is to investigate the modulatory effect of propofol on microRNAs in cancer therapy. Methods: This review was performed at PubMed, SCOPUS and Web of Science data-bases using keywords “propofol’, “microRNA”, “cancer therapy”, “propofol + microRNA” and “propofol + miR”. Results: It was found that propofol dually down-regulates/upregulates microRNAs to exert its antitumor activity. In terms of oncogenesis microRNAs, propofol exert an inhibitory effect, while propofol significantly enhances the expression of oncosuppressor microRNAs. Conclusion: It seems that propofol is a potential modulator of microRNAs and this capability can be used in the treatment of various cancers.

Arsenic, a naturally-occurring toxic element, and a traditionally-used drug, has received a great deal of attention worldwide due to its curative anti-cancer properties in patients with acute promyelocytic leukemia. Among the arsenicals, arsenic trioxide has been most widely used as an anti-cancer drug. Recent advances in cancer therapeutics have led to a paradigm shift away from traditional cytotoxic drugs towards the targeting of proteins closely associated with driving the cancer phenotype. Due to the diverse anti-cancer effects of ATO on different types of malignancies, numerous studies have made efforts to uncover the mechanisms of ATO-induced tumor suppression. From in vitro cellular models to studies in clinical settings, ATO has been extensively studied. The outcomes of these studies have opened doors to establishing improved molecular-targeted therapies for cancer treatment. The efficacy of ATO has been augmented by combination with other drugs. In this review, we discuss recent arsenic-based cancer therapies and summarize the novel underlying molecular mechanisms of the anti-cancer effects of ATO.

Cancer is one of the most complicated diseases in present-day medical science. Yearly, several studies suggest various strategies for preventing carcinogenesis. Furthermore, experiments for the treatment of cancer with low side effects are ongoing. Chemotherapy, targeted therapy, radiotherapy and immunotherapy are the most common non-invasive strategies for cancer treatment. One of the most challenging issues encountered with these modalities is low effectiveness, as well as normal tissue toxicity for chemo-radiation therapy. The use of some agents as adjuvants has been suggested to improve tumor responses and also alleviate normal tissue toxicity. Resveratrol, a natural flavonoid, has attracted a lot of attention for the management of both tumor and normal tissue responses to various modalities of cancer therapy. As an antioxidant and anti-inflammatory agent, in vitro and in vivo studies show that it is able to mitigate chemo-radiation toxicity in normal tissues. However, clinical studies to confirm the usage of resveratrol as a chemo-radioprotector are lacking. In addition, it can sensitize various types of cancer cells to both chemotherapy drugs and radiation. In recent years, some clinical studies suggested that resveratrol may have an effect on inducing cancer cell killing. Yet, clinical translation of resveratrol has not yielded desirable results for the combination of resveratrol with radiotherapy, targeted therapy or immunotherapy. In this paper, we review the potential role of resveratrol for preserving normal tissues and sensitization of cancer cells in combination with different cancer treatment modalities.

Background: The human sodium iodide symporter (hNIS) has been the most important target in nuclear medicine regarding thyroid-related diseases. Although hNIS-expression can also be determined in extra-thyroidal tumors, imaging hNIS with positron emission tomography has not been exploited clinically. Objective: Here, we evaluated the accumulation of the novel hNIS-substrate [18F]tetrafluoroborate ([18F]TFB) in the endogenously hNIS-expressing breast cancer cell line MCF-7 after an improved radiosynthesis and pharmacological stimulation. Methods: [18F]TFB was prepared under mild reaction conditions (40°C, 25 min) and its uptake properties were investigated in MCF-7 cells pretreated with a combination of all-trans retinoic acid plus methasone-derivatives and compared to the clinically established tracers [131I]iodide and [99mTc]pertechnetate. Specificity of the tracer accumulation was assessed by inhibition experiments using NaBF4, KSO3F, KI and KIO3. Results: [18F]TFB was obtained with a radiochemical yield of 24.0 ± 6.6 % (n = 17) within 40 min after high pressure liquid chromatography-separation and with 26.8 ± 6.2 % (n = 13) within 45 min after adapting the procedure on a synthesis module using higher starting activities (> 10 GBq). After pharmacological treatment, a 4-fold increase in hNIS-expression on the MCF-7 cell surface was achieved, resulting in a significantly higher [18F]TFB uptake into the cells (up to 58-fold) as compared to control experiments. Inhibition studies using various NIS-substrates confirmed the specificity of [18F]TFB for hNIS. Conclusion: [18F]TFB was shown to be a promising hNIS-substrate in our model using the human MCF-7 breast cancer cell line mandating in vivo evaluations in xenografted studies and in patients.

Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness. Objective: We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness. Methods: CDK12 expression level was accessed by using RT-qPCR and IHC. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation, FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through the c-myc/β-catenin pathway. Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell renewal and may serve as a potential biomarker of breast cancer prognosis. Conclusion: CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.