Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress

Reactive oxygen species (ROS) serve as critical signals in various cellular processes. Excessive ROS cause cell death or senescence and mediates the therapeutic effect of many cancer drugs. Recent studies showed that ROS increasingly accumulate during G2/M arrest, the underlying mechanism, however, has not been fully elucidated. Here, we show that in cancer cells treated with anticancer agent TH287 or paclitaxel that causes M arrest, mitochondria accumulate robustly and produce excessive mitochondrial superoxide, which causes oxidative DNA damage and undermines cell survival and proliferation. While mitochondrial mass is greatly increased in cells arrested at M phase, the mitochondrial function is compromised, as reflected by reduced mitochondrial membrane potential, increased SUMOylation and acetylation of mitochondrial proteins, as well as an increased metabolic reliance on glycolysis. CHK1 functional disruption decelerates cell cycle, spares the M arrest and attenuates mitochondrial oxidative stress. Induction of mitophagy and blockade of mitochondrial biogenesis, measures that reduce mitochondrial accumulation, also decelerate cell cycle and abrogate M arrest-coupled mitochondrial oxidative stress. These results suggest that cell cycle progression and mitochondrial homeostasis are interdependent and coordinated, and that impairment of mitochondrial homeostasis and the associated redox signaling may mediate the antineoplastic effect of the M arrest-inducing chemotherapeutics. Our findings provide insights into the fate of cells arrested at M phase and have implications in cancer therapy.

USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma

Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: 1) The emerging role of USP28 in cancer. 2) The complexity and mutational landscape of squamous tumors. 3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. 4) The development and current state of novel USP28 inhibitors.

Study of the antineoplastic effect of modulating apoptosis-related noncoding RNA in human hepatocellular carcinoma cell line (HepG2)

MiR-421 is considered an important molecule that can prevent tumor growth. Bioinformatics analysis indicated that mRNA caspase-3 gene is a target gene of miR-421. The current study aimed to explore the functional role of miR-421 in hepatocellular carcinoma (HCC) and explore the interaction between miR-421 and caspase-3. To validate bioinformatics data, RT-qPCR was used to detect the expression of miR-421 and caspase-3 in 10 HCC tissues. The results showed miR-421 expression was significantly higher in HCC than non HCC liver tissues (P<0.01), nevertheless caspase-3 gene expression was markedly lower in HCC than non HCC liver tissues (P<0.01). Besides, miR-421 expression was negatively associated with caspase-3 expression. MiR-421 mimic and inhibitor was transfected into HCC cell lines (HepG2). Proliferation assay, showed that low-expression of miR-421 inhibited the proliferation of HCC cells. RT-qPCR was worked for detection the expression levels of miR-421 and caspase-3 in HepG2 cells before and after transfection. The results showed that miR-421 expression in HepG2 cells was significantly lower in miR-421 inhibitor transfected group than in mimic- transfected and control groups (Mock) (P≤ 0.05), and caspase-3 gene expression in HCC tissues was markedly higher in inhibitor transfected group than those transfected by mimic and control group (Mock) (P≤0.05). Thus, miR-421 inhibitor may inhibit the proliferation of HCC cells via over- expression of caspase-3.

Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53–PUMA Apoptosis Pathway

Glioblastoma (GBM), the most lethal type of brain tumor in adults, has considerable cellular heterogeneity. The standard adjuvant chemotherapeutic agent for GBM, temozolomide (TMZ), has a modest response rate due to the development of drug resistance. Multiple studies have shown that valproic acid (VPA) can enhance GBM tumor control and prolong survival when given in conjunction with TMZ. However, the beneficial effect is variable. In this study, we analyzed the impact of VPA on GBM patient survival and its possible correlation with TMZ treatment and p53 gene mutation. In addition, the molecular mechanisms of TMZ in combination with VPA were examined using both p53 wild-type and p53 mutant human GBM cell lines. Our analysis of clinical data indicates that the survival benefit of a combined TMZ and VPA treatment in GBM patients is dependent on their p53 gene status. In cellular experiments, our results show that VPA enhanced the antineoplastic effect of TMZ by enhancing p53 activation and promoting the expression of its downstream pro-apoptotic protein, PUMA. Our study indicates that GBM patients with wild-type p53 may benefit from a combined TMZ+VPA treatment.

Metformin with standard neoadjuvant chemotherapy in breast carcinoma

Background Breast cancer is the most common cancer among women which increases after the age of 35 till it reaches a peak at 55-64 years. Metformin is a synthetic oral biguanide that has been shown to cause a 30% reduction in the lifetime risk of all cancers in diabetic patients on Metformin. We aimed at evaluating this antineoplastic effect in terms of pathological response, concurrent with standard neoadjuvant chemotherapy in breast cancer. Methodology 60 non-diabetic breast cancer patients receiving standard neoadjuvant chemotherapy at the breast cancer outpatient clinic, Ain Shams University hospital, were randomized into two arms (30 in each arm); Arm A Group receiving Metformin (850 mg bid) with standard line of neoadjuvant chemotherapy (FEC/Taxotere +/- Herceptin). Arm B Control group receiving the standard line of neoadjuvant chemotherapy alone. Results There’s a significant difference between Metformin and control arm in terms of response (complete and partial) versus no response (p = 0.03). Response to Metformin was significantly more pronounced in Luminal B subtype breast cancer (p = 0.03) and in grade II (p = 0.03). There’s no significant difference in toxicity between both arms; most common toxicities in both arms were vomiting (53.6%), nausea (30.4%) and neutropenia (30.4%) Conclusion Metformin has a significant antineoplastic effect which was measured in this study in terms of significant increase in pathological response concurrently with neoadjuvant chemotherapy in breast cancer compared to giving neoadjuvant chemotherapy alone.

Cordycepin, an adenosine analog Induces Apoptosis, ROS Generation, and Suppresses Mitochondrial potentials. Exhibits activities against Dalton’s Lymphoma.

Cordycepin exhibits anticancer potentials against various types of cancer cells. However, the multitudes of associated aspects of its anticancer properties against T- cell Lymphoma remains obscure. Based on in vitro studies, we reported that cordycepin exhibits an antineoplastic effect, against Dalton’s Lymphoma (DL) cells. This study illustrates antineoplastic effects and associated mechanisms of cordycepin against tumor cells withdrawn from murine T-cells Lymphoma, designated as Dalton’s Lymphoma. Our study reveals that cordycepin demonstrates tumoricidal activities against tumor cells via activating apoptosis and necrosis, including the surplus level of Reactive oxygen species production, declined mitochondrial membrane potentials, altered cell survival, and chromatin fragmentation. Moreover, this study also reported cordycepin-induced cell cycle arrest in tumor cells which further leads to apoptosis of tumor cells. This investigation elucidates the implication of antitumor actions of cordycepin against T- Cell Lymphoma accompanied by mitochondrial-dependent apoptotic pathway and therefore, have great medicinal significance.

Comparative EPR Study on the Scavenging Effect of Methotrexate with the Isomers of Its Photoswitchable Derivative

The scavenging effect of the antimetabolite dihydrofolate reductase inhibitor methotrexate (MTX) and the isomers of its photoswitchable derivate, cis- and trans-phototrexate (PHX), have been compared by ESR spectroscopy, with the application of a cyclic hydroxylamine spin probe. The results showed the most pronounced scavenging effect in the presence of trans-phototrexate (trans-PHX). At a low concentration (100 µM) cis-PHX also showed a greater scavenging effect than the parent molecule MTX. Direct antioxidant properties of the investigated molecules were measured by ABTS scavenging assay, which showed no significant difference between trans-PHX and cis-PHX, but both of the isomers of PHX showed a higher antioxidant capacity than MTX. These findings imply that trans-PHX may have more pronounced anti-inflammatory and tissue-protective effects than MTX, despite the lack of its cytotoxic, antineoplastic effect.

Piper nigrum based diet had a chemopreventive antineoplastic effect potentiated by Curcuma longa in C57BL/6 mice

Background: Medicinal plants represent a proven alternative strategy to treat cancer. Objective: To determine Curcuma longa (turmeric) and Piper nigrum (black pepper) effects in vitro and on the evolution of malignant melanoma B16F10 in C57BL/6 mice. Methods: 103 female mice divided in 4 groups: Control (n=44), Turmeric (n=20), Pepper (n=21), Turpepp (n=18). Turmeric 5% and/or pepper 0.5% were mixed with a dough made of pre-cooked cornmeal, eggs and coconut milkshake and given ad libitum to experimental groups as main diet; control received dough based diet. 200,000 melanoma cells were transplanted into right leg hind paw. Clinical, psychological, pathological and biochemical parameters were evaluated in vivo to measure melanoma progression. In vitro, metabolic activity was measured by quantifying anaerobic glycolysis and viability through MTT assay. Results: Combined preventive treatment with turmeric and pepper increased latency time for tumor onset, improved locomotor activity, preserved nociceptive response, decreased tumor volume and weight, reduced metastases and increased survival. These results were reproduced in the Pepper group, but with less statistical force; however, pepper showed greater potency in vitro experiments. Conclusion: Pepper showed an antineoplastic chemopreventive activity in B16F10 malignant melanoma, which was enhanced by the synergistic effect of turmeric.