Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?

Cancer has become a global health problem, accounting for one out of six deaths. Despite the recent advances in cancer therapy, there is still an ever-growing need for readily accessible new therapies. The process of drug discovery and development is arduous and takes many years, and while it is ongoing, the time for the current lead compounds to reach clinical trial phase is very long. Drug repurposing has recently gained significant attention as it expedites the process of discovering new entities for anticancer therapy. One such potential candidate is the antimalarial drug, artemisinin that has shown anticancer activities in vitro and in vivo. In this review, major molecular and cellular mechanisms underlying the anticancer effect of artemisinin and its derivatives are summarised. Furthermore, major mechanisms of action and some key signaling pathways of this group of compounds have been reviewed to explore potential targets that contribute to the proliferation and metastasis of tumor cells. Despite its established profile in malaria treatment, pharmacokinetic properties, anticancer potency, and current formulations that hinder the clinical translation of artemisinin as an anticancer agent, have been discussed. Finally, potential solutions or new strategies are identified to overcome the bottlenecks in repurposing artemisinin-type compounds as anticancer drugs.

User Preferences and Persona Design for an mHealth Intervention to Support Adherence to Cardiovascular Disease Medication in Singapore: A Multi-Method Study.

BACKGROUND: The use of mobile health (mHealth) has gained popularity globally, including for its use in a variety of health interventions, particularly through short message service (SMS) text messaging. However, there are challenges to the use of mHealth, particularly among older users who have a large heterogeneity in usability and accessibility barriers when using technology. OBJECTIVE: In order to better understand and conceptualize the diversity of users and give insight into their particular needs, we turned to persona creation. Personas are user archetypes created through data generated from multi-method inquiry with actual target users. Personas are an appropriate yet largely underutilized component of current mHealth research. METHODS: Leveraging data from a multi-method study conducted in Singapore with an ethnically diverse population including Chinese, Malay, and Indian participants, we used a proforma to analyze data from the qualitative component (ie, 20 in-depth interviews) and quantitative component (ie, 100 interviewer-guided surveys). We then identified key characteristics, including technology use and preferences as well as adherence factors, to synthesize five personas reflective of persons over the age of 40 years in Singapore with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk factors, such as hypertension. RESULTS: We present five personas typologized as (1) The Quiet Analog, (2) The Busy Grandparent, (3) The Socializer, (4) The Newly Diagnosed, and (5) The Hard-to-Reach. We report on four key characteristics: health care access, medication adherence, mobile phone technology usage (ie, ownership, access, and utilization), and interest in mHealth. Finally, we provide insights into how these personas may be used in the design and implementation of an mHealth intervention. Our work demonstrates how multi-method data can create biopsychosocial personas that can be used to explore and address the diversity in behaviors, preferences, and needs in user groups. CONCLUSIONS: With wider adoption of mHealth, it is important that we consider user-centered design techniques and design thinking in order to create meaningful, patient-centered interventions for adherence to medications. Future research in this area should include greater exploration of how these five personas can be used to better understand how and when is best to deliver mHealth interventions in Singapore and beyond.

Perspectives on Acceptance and Use of a Mobile Health Intervention for the Prevention of Atherosclerotic Cardiovascular Disease in Singapore: Mixed-Methods Study.

BACKGROUND: Cardiovascular disease, including atherosclerotic cardiovascular disease (ASCVD), is a growing public health threat globally and many individuals remain undiagnosed, untreated, and uncontrolled. Simultaneously, mobile health (mHealth) interventions using short messaging service (SMS) have gained popularity globally. There is an opportunity for innovative approaches such as mHealth to encourage and enable adherence to medications for ASCVD and its risk factors. OBJECTIVE: This study aimed to understand mobile technology acceptance, use, and facilitating conditions among the study population ahead of the design of an mHealth intervention. METHODS: Using data from a mixed-methods study conducted in Singapore, we conducted a cross-sectional survey with 100 participants and in-depth, semistructured interviews with 20 patients. All participants were over the age of 40 years with ASCVD or its risk factors. Interviews were conducted in English and Mandarin and if needed translated to English. Nvivo 11 (QSR International) was used for analyses. RESULTS: Participants reported their perspectives on technology use and preferences, including low or sporadic mobile phone use and usability concerns including small screen and text size, among others; the benefit of previous mHealth use in creating a favorable opinion of SMS for health information; trust in both the source of mHealth SMS, as well as in treatment; the formation of habits; and fear of sequelae or death for facilitating intention to use an mHealth intervention and adhere to medication. We also highlighted a case that underscored the importance of the period after diagnosis in habit forming as an opportunity for an mHealth intervention. CONCLUSIONS: We explored both technology- and adherence-related factors that influence a patient's intention to use an mHealth intervention for adherence to ASCVD medication in Singapore. We highlighted the importance of identifying the right opportunity to engage with patients and promote an mHealth intervention for adherence, such as immediately following diagnosis when patients are establishing medication-taking habits.

A novel combinatorial strategy using Seliciclib(®) and Belinostat(®) for eradication of non-small cell lung cancer via apoptosis induction and BID activation.

With conventional anticancer agents for non-small cell lung cancer (NSCLC) reaching therapeutic ceiling, the novel combination using histone deacetylase inhibitor, PXD101 (Belinostat(®)), and CDK inhibitor, CYC202 (Seliciclib(®)), was investigated as an alternative anticancer strategy. At clinically achievable concentration of CYC202 (15 µM), combination therapy resulted in significant reduction in cell proliferation (IC50 = 3.67 ± 0.80 µM, p < 0.05) compared with PXD101 alone (IC50 = 6.56 ± 0.42 µM) in p53 wild-type A549 cells. Significant increase in apoptosis that occurred independently of cell cycle arrest was observed after concurrent treatment. This result was corroborated by greater formation of cleaved caspase-8, caspase-3 and PARP. Up-regulation of p53 and truncated BID protein levels was seen while Mcl-1 and XIAP protein levels were down-regulated upon combined treatment. Further analysis of apoptotic pathways revealed that caspase inhibitors, but not p53 silencing, significantly abrogated the cytotoxic enhancement. Moreover, the enhanced efficacy of this combination was additionally confirmed in p53 null H2444 cells, suggesting the potential of this combination for treatment of NSCLC that are not amenable to effects of conventional p53-inducing agents.

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development.

Nimbolide is one of the main components in the leaf extract of Azadirachta indica (A. indica). Accumulating evidence from various in vitro and in vivo studies indicates that nimbolide possesses potent anticancer activity against several types of cancer and also shows potential chemopreventive activity in animal models. The main mechanisms of action of nimbolide include anti-proliferation, induction of apoptosis, inhibition of metastasis and angiogenesis, and modulation of carcinogen-metabolizing enzymes. Although multiple pharmacodynamic (PD) studies have been carried out, nimbolide is still at the infant stage in the drug development pipeline due to the lack of systematic pharmacokinetic (PK) studies and long-term toxicological studies. Preclinical PK and toxicological studies are vital in determining the dosage range to support the safety of nimbolide for first-in-human clinical trials. In this review, we will provide a comprehensive summary for the current status of nimbolide as an anticancer and chemopreventive lead compound, and highlight the importance of systematic preclinical PK and toxicological studies in accelerating the process of application of nimbolide as a therapeutic agent against various malignancies.

Quantification of the resveratrol analogs trans-2,3-dimethoxy-stilbene and trans-3,4-dimethoxystilbene in rat plasma: application to pre-clinical pharmacokinetic studies.

trans-2,3-Dimethoxystilbene (2,3-DMS) and trans-3,4-dimethoxystilbene (3,4-DMS) are two synthetic resveratrol (trans-3,5,4'-trihydroxystilbene) analogs. In this study, a simple HPLC method was developed and validated to determine 2,3-DMS and 3,4-DMS in rat plasma. Chromatographic separation was obtained with a reversed-phase HPLC column through a 12.5-min gradient delivery of a mixture of acetonitrile and water at the flow rate of 1.5 mL/min at 50 °C. The lower limit of quantification was 10 ng/mL. After successful validation, the pharmacokinetic profiles of 2,3-DMS and 3,4-DMS were subsequently studied in Sprague-Dawley rats. Upon single intravenous administration (4 mg/kg), 2,3-DMS had a medium volume of distribution of the central compartment (Vc = 2.71 ± 0.51 L/kg), quite rapid clearance (Cl = 52.0 ± 7.0 mL/min/kg), moderate mean transit time (MTT0→last = 131.0 ± 4.5 min) but a fairly long terminal elimination half-life (t1/2 λZ = 288.9 ± 92.9 min). Interestingly, 3,4-DMS displayed a pharmacokinetic profile apparently distinct from 2,3-DMS and it had more extensive distribution (Vc = 5.58 ± 1.73 L/kg), faster clearance (Cl = 143.4 ± 40.5 mL/min/kg) and shorter residence (MTT0→last = 61.4 ± 27.1 min). Following single oral administration (10 mg/kg), 2,3-DMS had low and erratic plasma exposure (Cmax = 37.5 ± 23.7 ng/mL) and poor oral bioavailability (2.22% ± 2.13%) while the oral bioavailability of 3,4-DMS was even poorer than 2,3-DMS. Clearly, the location of the methoxy groups had a significant impact on the pharmacokinetics of resveratrol analogs. This study provided useful information for the design of resveratrol derivatives in future study.

Association of eleven common, low-penetrance colorectal cancer susceptibility genetic variants at six risk loci with clinical outcome.

BACKGROUND: Low-penetrance genetic variants have been increasingly recognized to influence the risk of tumor development. Risk variants for colorectal cancer (CRC) have been mapped to chromosome positions 8q23.3, 8q24, 9p24.1, 10p14, 11q23, 14q22.2, 15q13, 16q22.1, 18q21, 19q13.1 and 20p12.3. In particular, the 8q24 single nucleotide polymorphism (SNP), rs6983267, has reproducibly been associated with the risk of developing CRC. As the CRC risk SNPs may also influence disease outcome, thus in this study, we evaluated whether they influence patient survival. METHODOLOGY/PRINCIPAL FINDINGS: DNA samples from 583 CRC patients enrolled in the prospective, North Carolina Cancer Care Outcomes Research and Surveillance Consortium Study (NC CanCORS) were genotyped for 11 CRC susceptibility SNPs at 6 CRC risk loci. Relationships between genotypes and patient survival were examined using Cox regression analysis. In multivariate analysis, patients homozygous for the CRC risk allele of rs7013278 or rs7014346 (both at 8 q24) were only nominally significant for poorer overall survival compared to patients homozygous for the protective allele (hazard ratio = 2.20 and 1.96, respectively; P<0.05). None of these associations, however, remained statistically significant after correction for multiple testing. The other nine susceptibility SNPs tested were not significantly associated with survival. CONCLUSIONS/SIGNIFICANCE: We did not find evidence of association of CRC risk variants with patient survival.

Synergistic effects of suberoylanilide hydroxamic acid combined with cisplatin causing cell cycle arrest independent apoptosis in platinum-resistant ovarian cancer cells.

Histone deacetylase inhibitors (HDACIs) belong to an emerging class of anticancer compounds. It is increasingly recognized that their unique and complementary mode of action make HDACIs valuable agents in augmenting the cytotoxicity of conventional chemotherapeutics. We examined the potential for combined use of an approved HDACI, suberoylanilide hydroxamic acid (SAHA), with cisplatin (Cddp) in platinum-resistant ovarian cancer cells, OVCAR-3 and SKOV-3. The nature of the drug interaction following combinatory therapy was assessed using median effect analysis. We found that SAHA acted synergistically with Cddp over a wide range of concentrations in both cell types, resulting in favorable dose reductions of both compounds. In particular, in the more Cddp-resistant SKOV-3 cells, more than 8-fold dose reduction of Cddp was achieved with the simultaneous use of SAHA and Cddp as compared to the dose required to elicit similar cell kill effects using Cddp alone. More importantly, therapeutic selectivity for ovarian cancer cells over normal fibroblast cells were maintained with the combinatorial therapy. We further observed that the augmentation of Cddp-induced cell death was mediated by the net increase in apoptosis and was independent of cell cycle arrest. Overall, concurrent application of SAHA and Cddp yielded the most favorable cell kill, indicating that this combination is promising for treatment of platinum-resistant ovarian tumors.

Microarray analysis revealed dysregulation of multiple genes associated with chemoresistance to As(2)O(3) and increased tumor aggressiveness in a newly established arsenic-resistant ovarian cancer cell line, OVCAR-3/AsR.

The potential of arsenic trioxide (As(2)O(3)) for use as a novel therapy for ovarian cancer treatment has been increasingly recognized. In this study, we developed an arsenic-resistant OVCAR-3 subline (OVCAR-3/AsR) and aimed to identify the molecular mechanisms and signaling pathways contributing to the development of acquired arsenic chemoresistance in ovarian cancer. OVCAR-3/AsR cells were obtained following continual exposure of parental OVCAR-3 cells to low dose As(2)O(3) for 12months. Cytotoxicity of OVCAR-3/AsR cells to As(2)O(3), paclitaxel and cisplatin was investigated. Cell apoptosis and cell cycle distribution following As(2)O(3) treatment of OVCAR-3/AsR cells was also analyzed using flow cytometry. Subsequently, cDNA microarray analysis was performed from the RNA samples of OVCAR-3 and OVCAR-3/AsR cells in duplicate experiments. Microarray data were analyzed using Genespring® and Pathway Studio® Softwares. OVCAR-3/AsR cells showed 9-fold greater resistance to As(2)O(3) and lack of collateral resistance to cisplatin and paclitaxel. Compared with parental OVCAR-3 cells, OVCAR-3/AsR had significantly lower apoptotic rates following As(2)O(3) treatment. These cells were also arrested at both the S phase and G(2)/M phase of the cell cycle after exposure to high concentrations of As(2)O(3). Gene expression profiling revealed significant differences in expression levels of 397 genes between OVCAR-3/AsR and OVCAR-3 cells. The differentially regulated transcripts genes have functional ontologies related to continued cancer cell growth, cell survival, tumor metastasis and tumor aggressiveness. Additionally, numerous gene targets of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor showed elevated expression in OVCAR-3/AsR cells. Subsequent pathway analysis further revealed a gene network involving interleukin 1-alpha (IL1A) in mediating the arsenic-resistant phenotype. These results showed that changes in multiple genes and an increased in tumor aggressiveness occurred during the development of acquired chemoresistance to As(2)O(3) in ovarian cancer cells. The functional relevance of these genetic changes should be validated in future studies.

Differential augmentative effects of buthionine sulfoximine and ascorbic acid in As2O3-induced ovarian cancer cell death: oxidative stress-independent and -dependent cytotoxic potentiation.

The potential of arsenic trioxide (As2O3) as a novel therapy against ovarian cancer has been progressively recognized. Its prospective usefulness for treatment of this malignancy either alone or in combination with other chemotherapeutic agents has been increasingly explored. In this study, we attempted to enhance the cytotoxicity of As2O3 in ovarian cancer cells through manipulation of cellular glutathione (GSH) levels using either buthionine sulfoximine (BSO) or ascorbic acid (AA). Results from our studies showed that combinatorial therapies using As2O3 with either low dose BSO or only pharmacological doses of AA acted synergistically to enhance the cytotoxicity of As2O3 in ovarian tumor cells. With these regimens, therapeutic selectivity was observed with preferential killing of ovarian tumor cells over normal fibroblast controls. Furthermore, contrary to previous reports, enhancement of As2O3-mediated cell killing by these two agents was propagated through different effects. With BSO, apoptotic and non-apoptotic cell death enhancement were mediated through increased arsenic accumulation and GSH depletion that occurred independently of reactive oxygen species. With pharmacological doses of AA, increase in cell death proceeded through non-apoptotic routes via an oxidative stress-related pathway independent of GSH levels. Taken together, these results indicate that GSH depleting agents or pro-oxidative chemicals have capabilities of improving the utility of As2O3 in ovarian cancer management.

Current trends in modern pharmaceutical analysis for drug discovery.

Traditionally, pharmaceutical analysis referred to the chemical analysis of drug molecules. However, over the years, modern pharmaceutical analysis has evolved beyond this to encompass combination techniques, high-throughput technologies, chemometrics, microdosing studies, miniaturization and nanotechnology. These analytical advances are now being employed in all stages of drug discovery and the focus of this review will be on how these technologies are being employed within this process. With new, improved and evolving technologies, as well as new applications for existing technology, the search for new drugs for the prevention and treatment of human diseases continues.