Current Cancer Drug Targets - Volume 21, Issue 6, 2021

Background: Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer and associated with a poor prognosis. Only one-third of CCA cases are diagnosed at operable stages. However, a high rate of relapse has been observed postoperatively. Besides screening for operable individuals, efficacious therapeutic for recurrent and advanced CCA is urgently needed. The treatment outcome of available therapeutics is important to clarify clinical indication and facilitate the development of treatment strategies. Objective: This review aims to compare the treatment outcome of different therapeutics based on both overall survival and progression-free survival. Methods: Over one hundred peer-reviewed articles were examined. We compared the treatment outcome between different treatment methods, including tumor resection with or without postoperative systematic therapy, chemotherapies including FOFLOX, and targeted therapies, such as IDH1, K-RAS, and FGFR inhibitors. Notably, the scientific basis and outcome of available treatment methods were compared with the standard first-line therapy. Results: CCAs at early stages should firstly undergo tumor resection surgery, followed by postoperative treatment with Capecitabine. Chemotherapy can be considered as a preoperative option for unresectable CCAs. Inoperable CCAs with genetic aberrances like FGFR alterations, IDH1, and KRAS mutations should be considered with targeted therapies. Fluoropyrimidine prodrug (S-1)/Gemcitabine/Cisplatin and nab-Paclitaxel/Gemcitabine/Cisplatin show favorable outcome which hints at the triplet regimen to be superior to Gemcitabine/Cisplatin on CCA. The triplet chemotherapeutic should be tested further compared to Gemcitabine/Cisplatin among CCAs without genetic alterations. Gemcitabine plus S-1 was recently suggested as the convenient and equivalent standard first-line for advanced/recurrent biliary tract cancer. Conclusion: This review provides a comparative outcome between novel targeted therapies and currently available therapeutics.

The interplay between cancer and obesity is multifactorial and complex with the increased risk of cancer development in obese individuals posing a significant threat. Obesity leads to the upregulation or hyperactivation of several oncogenic pathways in cancer cells, which drives them towards a deleterious phenotype. The cross-talk between cancer and obesity is considered a large contributing factor in the development of chemotherapeutic drug resistance and the resistance to radiotherapy. The link between obesity and the development of cancer is so strong that a medication that demonstrates effectiveness against both conditions would serve as an essential step. In this context, anti-obesity medications provide a worthy list of candidates based on their chemo-preventive potential and chemotherapeutic properties. The current study focuses on exploring the potential of anti-obesity medicines as dual anticancer drugs. These medications target several key signaling pathways (e.g., AMPK, PI3K/Akt/mTOR, MAPK, NF-ΚB, JNK/ERK), which prove to be crucial for both cancer growth and metastases. Some of these drugs also play an important role in attenuating the signaling and cellular events which incite cancer-obesity cross-talk and demonstrate efficient counteraction of neoplastic transformation. Thus, this review highlights a comprehensive view of the potential use of anti-obesity medicines to treat both cancer and obesity for patients exhibiting both comorbities.

Background: Redox dysregulation originating from metabolic alterations in cancer cells contributes to their proliferation, invasion, and resistance to therapy. Conversely, these features represent a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. Amongst them, Vitamin K (VitK) carries the potential against cancer stem cells, in addition to the rest of tumor mass. Objectives: To assess the possible benefits and safety of VitK for cancer treatment using a systematic review and meta-analysis with a mixed-methods approach. Methods: We performed a systematic search on several electronic databases for studies comparing VitK treatment with and without combination to the control groups. For quantitative studies, fully or partially reported clinical outcomes such as recurrence rates, survival, overall response and adverse reactions were assessed. For qualitative studies, a narrative synthesis was accomplished. Results: Our analysis suggested that the clinical outcome of efficacy, the pooled hazard ratio for progression-free survival, and the pooled relative risk for overall survival, and overall response were significantly higher in the VitK therapy group compared to the placebo group (p<0.05). We did not observe any significant difference in the occurrence of adverse events between groups. Among qualitative studies, VitK treatment targeting myelodysplastic syndrome and advanced solid tumors resulted in 24.1% and 10% of clinical response, respectively. Conclusion: VitK not only exerts antitumor effects against a wide range of tumor types, but it also has excellent synergism with other therapeutic agents.

Aim: The study is aimed at examining of action of iron, DOX, and their complex on the Mitochondrial Permeability Transition Pore (MPTP) opening and detecting of possible protectors of MPTP in the conditions close to mitochondria-dependent ferroptosis. Background: The Toxicity of Doxorubicin (DOX) is mainly associated with free iron accumulation and mitochondrial dysfunction. DOX can provoke ferroptosis, iron-dependent cell death driven by membrane damage. The Mitochondrial Permeability Transition Pore (MPTP) is considered as a common pathway leading to the development of apoptosis, necrosis, and, possibly, ferroptosis. The influence of DOX on the Ca²⁺ -induced MPTP opening in the presence of iron has not yet been studied. Objective: The study was conducted on isolated liver and heart mitochondria. MPTP and succinate- ubiquinone oxidoreductase were studied as targets of DOX in mitochondria-dependent ferroptosis. The iron chelator deferoxamine (DFO), the lipid radical scavenger butyl-hydroxytoluene (BHT), and rutenium red (Rr), as a possible inhibitor of ferrous ions uptake in mitochondria, were tested as MPTP protectors. The role of medium alkalization was also examined. Methods: Changes of threshold calcium concentrations required for MPTP opening were measured by a Ca²⁺ selective electrode, mitochondrial membrane potential was registered by tetraphenylphosphonium (TPP+)-selective electrode, and mitochondrial swelling was recorded as a decrease in absorbance at 540 nm. The activity of Succinate Dehydrogenase (SDH) was determined by the reduction of the electron acceptor DCPIP. Conclusion: MPTP and the respiratory complex II are identified as the main targets of the iron-dependent action of DOX on the isolated mitochondria. All MPTP protectors tested abolished or weakened the effect of iron and a complex of iron with DOX on Ca²⁺ -induced MPTP opening, acting in different stages of MPTP activation. These data open new approaches to the modulation of the toxic influence of DOX on mitochondria with the aim to reduce their dysfunction.

Background: The role and mechanism of long non-coding RNA cytoskeleton regulator (CYTOR) in Invasive Pituitary Adenomas (IPA) have not been elucidated previously. Objective: This study aimed to investigate the interaction between CYTOR and miR-206 and their roles in IPA using HP75 cells as the model. Methods: The expression levels of CYTOR and miR-206 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in IPA tissues and cell lines. The Chi-square test was used to analyze the correlation between CYTOR expression and clinical-pathological parameters. HP75 cell proliferation was detected by Cell Counting Kit-8 assay and colony formation assay. Scratch healing experiments and Transwell assay were used to detect migration and invasion of HP75 cells. The relationship between CYTOR and miR-206 was predicted by bioinformatics and verified by qRT-PCR and the dual-luciferase reporter gene method. Results: CYTOR is up-regulated in IPA tissues and cell lines. The high expression of CYTOR is associated with adenoma invasiveness and adenoma size of the patients. Down-regulation of CYTOR decreases the proliferation, migration and invasion of HP75 cells, while up-regulation of miR-206 can inhibit proliferation, migration and invasion of HP75 cells. MiR-206 is identified as a target of CYTOR and could be negatively regulated by it in IPA. Discussion: CYTOR, as a tumor-promoting factor, facilitates the proliferation, migration and invasion of HP75 cells through sponging miR-206. Conclusion: The CYTOR-miR-206 axis provides new insights into the diagnosis and treatment of IPA.

Background: This study aims to investigate the relation between Survivin gene polymorphisms and the risk of Hepatocellular carcinoma (HCC) resulting from hepatitis C infection among the Egyptian population. Methods: This prospective study was conducted on 164 patients, 57 patients were diagnosed with hepatitis C, where 57 were diagnosed with HCC in addition to 50 healthy volunteers as controls. Genotyping for Survivin rs1042489 and rs8073069 single nucleotide polymorphisms was carried out by the allelic discrimination Real-Time Polymerase Chain Reaction Single Nucleotide Polymorphisms genotyping technology. Results: The results of Survivin rs1042489 polymorphism revealed that the TC and CC genotypes were significantly different between hepatocellular carcinoma patients (OR=15.5, 95%CI: 3.299-72.825,P<0.001), and controls (OR=44, 95%CI: 8.025-241.254, P<0.001). Furthermore, CC genotype was significantly different between cirrhotic and hepatocellular carcinoma patients (OR=19.2, 95%CI: 3.097-119.049, P=0.002). Moreover, the TC genotype shows a significant difference between controls and cirrhotic patients (OR=5.5, 95%CI: 2.111-14.328, P<0.001). However, when comparing TT genotypes, CC+TC genotypes results showed a significant association with increasing the risk of cirrhosis and hepatocellular carcinoma (OR=4.812, 95%CI: 1.893-12.233, P=0.001), (OR=21.607, 95%CI: 4.738-98.532, P<0.01), respectively. On the other hand, there was no significant difference among all studied groups for all genotypes regarding Survivin rs8073069. Also, the CC+GC genotype showed no significant association with increased risk of hepatocellular carcinoma (P=0.999) compared with the GG genotypes. Conclusion: The study indicates that functional Survivin rs1042489 polymorphism may contribute to the risk of hepatocellular carcinoma while Survivin rs8073069 polymorphism has no significant association with increased risk of hepatocellular carcinoma among the studied groups.