Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve a synergistic effect that boosts cytotoxicity to cancer cells. In cancer, aberrant apoptotic pathways allow cells that should be killed to survive with genetic abnormalities, leading to cancer progression. Mutations in apoptotic mechanism arising during the treatment of cancer through cancer progression can consequently lead to chemoresistance. Natural compound mixtures that are believed to have multiple specific targets with minimal acceptable side-effects are now of interest to many researchers due to their cytotoxic and chemosensitizing activities. Synergistic interactions within a drug mixture enhance the search for potential molecular targets in cancer cells. Nonetheless, biased/flawed scientific evidence from natural products can suggest false positive therapeutic benefits during drug screening. In this review, we have taken these factors into consideration when discussing the evidence for these compounds and their synergistic therapeutic benefits in cancer. While there is limited evidence for clinical efficacy for these mixtures, in vitro data suggest that these preparations merit further investigation, both in vitro and in vivo.

Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action

EMT in cervical cancer: Its role in tumour progression and response to therapy

An enigmatic question exists concerning the pro- or anti-cancer status of mesenchymal stem cells (MSCs). Despite growing interest, this question remains unanswered, and the debate became intensified with new evidences backing each side. Here, we showed that human adipose MSC (hAMSC)-derived conditioned medium (CM) exhibited inhibitory effects on A2780 human ovarian cancer cells by blocking the cell cycle, and activating mitochondria-mediated apoptosis signalling. Explicitly, we demonstrated that exosomes, an important biological component of hAMSC-CM, could restrain proliferation, wound-repair and colony formation ability of A2780 and SKOV-3 cancer cells. Furthermore, hAMSC-CM-derived exosomes induced apoptosis signalling by upregulating different pro-apoptotic signalling molecules, such as BAX, CASP9, and CASP3, as well as downregulating the anti-apoptotic protein BCL2. More specifically, cancer cells exhibited reduced viability following fresh or protease-digested exosome treatment; however, treatment with RNase-digested exosomes could not inhibit the proliferation of cancer cells. Additionally, sequencing of exosomal RNAs revealed a rich population of microRNAs (miRNAs), which exhibit anti-cancer activities by targeting different molecules associated with cancer survival. Our findings indicated that exosomal miRNAs are important players involved in the inhibitory influence of hAMSC-CM towards ovarian cancer cells. Therefore, we believe that these comprehensive results will provide advances concerning ovarian cancer research and treatment.

Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells.

Cervical cancer is as a kind of cancer beginning from the cervix. Given that cervical cancer could be observed in women who infected with papillomavirus, regular oral contraceptives, and multiple pregnancies. Early detection of cervical cancer is one of the most important aspects of the therapy of this malignancy. Despite several efforts, finding and developing new biomarkers for cervical cancer diagnosis are required. Among various prognostic, diagnostic, and therapeutic biomarkers, miRNA have been emerged as powerful biomarkers for detection, treatment, and monitoring of response to therapy in cervical cancer. Here, we summarized various miRNAs as an employable platform for prognostic, diagnostic, and therapeutic biomarkers in the treatment of cervical cancer.

microRNAs: New prognostic, diagnostic, and therapeutic biomarkers in cervical cancer.

The growing incidence of microorganisms that resist antimicrobials is a constant concern for the scientific community, while the development of new antimicrobials from new chemical entities has become more and more expensive, time-consuming, and exacerbated by emerging drug-resistant strains. In this regard, many scientists are conducting research on plants aiming to discover possible antimicrobial compounds. The secondary metabolites contained in plants are a source of chemical entities having pharmacological activities and intended to be used for the treatment of different diseases. These chemical entities have the potential to be used as an effective antioxidant, antimutagenic, anticarcinogenic and antimicrobial agents. Among these pharmacologically active entities are the alkaloids which are classified into a number of classes, including pyrrolizidines, pyrrolidines, quinolizidines, indoles, tropanes, piperidines, purines, imidazoles, and isoquinolines. Alkaloids that have antioxidant properties are capable of preventing a variety of degenerative diseases through capturing free radicals, or through binding to catalysts involved indifferent oxidation processes occurring within the human body. Furthermore, these entities are capable of inhibiting the activity of bacteria, fungi, protozoan and etc. The unique properties of these secondary metabolites are the main reason for their utilization by the pharmaceutical companies for the treatment of different diseases. Generally, these alkaloids are extracted from plants, animals and fungi. Penicillin is the most famous natural drug discovery deriving from fungus. Similarly, marines have been used as a source for thousands of bioactive marine natural products. In this review, we cover the medical use of natural alkaloids isolated from a variety of plants and utilized by humans as antibacterial, antiviral, antifungal and anticancer agents. An example for such alkaloids is berberine, an isoquinoline alkaloid, found in roots and stem-bark of Berberis asculin P. Renault plant and used to kill a variety of microorganisms.

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The Biological Activity of Natural Alkaloids against Herbivores, Cancerous Cells and Pathogens.

MicroRNAs were demonstrated to play an important role in the regulation of gene expression. Here, we showed that miR-99a and -99b (miR-99a/b) were down-regulated in human cervical cancer patient tissues and were negatively related with lymphatic metastasis. In addition, overexpression of miR-99a/b inhibited cell growth and invasion, whereas suppression of miR-99a/b yielded the reverse phenotype. Dual luciferase report assay revealed that mTOR was identified as a novel target gene of both miR-99a and -99b. Altogether, these results suggested that miR-99a/b directly and negatively regulated mTOR expression in cervical cancer cells, and enforced the importance of miR-99a/b and their targets in the malignant phenotypes of cervical carcinogenesis.

miR-99a and -99b inhibit cervical cancer cell proliferation and invasion by targeting mTOR signaling pathway

EphB2 promotes cervical cancer progression by inducing epithelial-mesenchymal transition

RAD51 is one of the pivotal enzymes for DNA double-strand break (DSB) repair by the homologous recombination (HR) pathway, which implies it as a promising and novel target for cancer therapy. Recent findings have indicated RAD51 protein is overexpressed in a variety of tumors. The high-expression of RAD51 is related to poor prognosis. RAD51 is involved in the repair of DNA damage and the generation of genetic diversity by an evolutionarily conserved mechanism. However, the exact mechanism of Rad51 in the progression of cervical cancer remains unclear. RI-1 is a small molecule that inhibits the central recombination protein RAD51. In this study, we found that RAD51 was highly expressed in invasive squamous cervical cancer (SCC). The administration of RI-1 inhibited cell growth in vitro and reduced growth of tumor xenografts in vivo with cervical cancer cells (HeLa and SiHa). Further investigation suggested that RAD51 protein significantly promoted the cell cycle transition from the G0/G1 to S phase. In addition, the inhibition of RAD51 reduced the level of the cell cycle related protein cyclin D1, but increased the levels of p21 mRNA and protein. As a DNA DSB repair enzyme, the expression of RAD51 in tumor cells possibly affects their sensitivity to anti-cancer agents. Additionally, in experiments using cisplatin and ionizing radiation, RI-1 treated cervical cancer cells, HeLa and SiHa, were sensitized to a greater extent than the untreated control. Thus, HR inhibition of RAD51 may provide yet another mechanism of therapeutic target for the chemosensitization and radiosensitization of cervical cancer with RI-1. Collectively, our data demonstrated for the first time that inhibition of RAD51 suppressed the cervical cancer cell proliferation and the growth of cervical cancer xenografts by attenuating cell cycle transition, which could be a functional link between RAD51 and cyclin D1 and p21.

/pdf/the-homologous-recombination-protein-rad51-is-a-promising-44voxvs91k.pdf

The homologous recombination protein RAD51 is a promising therapeutic target for cervical carcinoma

Hiwi, also named PiwiL1, is a human homologue of the Piwi family which is associated with stem cells and is overexpressed in several types of cancers. In the present study, we aimed to investigate the role of Hiwi in cervical carcinogenesis. Immunochemical analysis showed a significantly higher frequency of Hiwi staining in high-grade squamous intraepithelial lesions (HSILs) and cervical cancer tissues when comparing with the frequency in normal cervices. Particularly, Hiwi staining was restricted to basal cells of the normal cervix and was associated with the progression of cervical cancer and chemotherapy resistance. We further found that ectopic Hiwi increased the chemical resistance in SiHa cells, and silencing of Hiwi in HeLa cells decreased the cell viability. In addition, as a cancer stem cell marker, Hiwi promoted the tumorsphere formation in vitro and tumorigenicity in vivo and elevated the expression of several stem cell self-renewal-associated transcription factors, in spite of inhibited the proliferation. These results suggest that Hiwi may participate in the carcinogenesis of cervical cancer and may be a potential therapeutic target molecule for cervical cancers.

/pdf/hiwi-facilitates-chemoresistance-as-a-cancer-stem-cell-4k3i6yigwp.pdf

Hiwi facilitates chemoresistance as a cancer stem cell marker in cervical cancer

Oxymatrine is an alkaloid obtained primarily from Sophora roots and has been shown to show anticancer effects in various cancers. However, the cellular and molecular effects of this agent on cervical cancer have been poorly characterized. Here, we investigated the antitumor effect of oxymatrine on a human cervical cancer cell line (HeLa). Our results showed that application of oxymatrine significantly inhibited the cell growth and tumorigenesis in a dose-dependent manner and induced apoptosis through caspase-dependent pathways as determined using flow cytometry and TUNEL staining analysis. To define the proteins potentially related to the mechanisms of action, proteomic analysis was utilized to detect proteins altered by oxymatrine. As the downregulated gene, inosine monophosphate dehydrogenase type II (IMPDH2) was responsible for oxymatrine-induced mitochondrial-related apoptosis. Moreover, oxymatrine depleted intracellular guanosine 5'-triphosphate (GTP) levels by effective IMPDH inhibition. Functional analyses further showed that oxymatrine and tiazofurin, an inhibitor of IMPDH2, sensitized resistant HeLa/DDP cells to cisplatin. In addition, the expression of IMPDH2 in cervical cancer was significantly higher than that in the normal cervical epithelium. Taken together, these findings suggest that targeting of IMPDH2 by potential pharmacological inhibitors, oxymatrine in combination with chemotherapy, might be a promising means of overcoming chemoresistance in cervical cancer with high IMPDH2 expression, and may thus provide new insights into the mechanism of oxyamtrine-induced anticancer effects.

Mu Li

Papers

miR-99a and -99b inhibit cervical cancer cell proliferation and invasion by targeting mTOR signaling pathway

EphB2 promotes cervical cancer progression by inducing epithelial-mesenchymal transition

The homologous recombination protein RAD51 is a promising therapeutic target for cervical carcinoma

Hiwi facilitates chemoresistance as a cancer stem cell marker in cervical cancer

Oxymatrine induces apoptosis in human cervical cancer cells through guanine nucleotide depletion.