Synergistic anticancer effects of doxorubicin and metformin combination therapy: A systematic review.

INTRODUCTION: Doxorubicin (DOX) a chemotherapy drug often leads to the development of resistance, in cancer cells after prolonged treatment. Recent studies have suggested that using metformin plus doxorubicin could result in synergic effects. This study focuses on exploring the co-treat treatment of doxorubicin and metformin for various cancers. METHOD: Following the PRISMA guidelines we conducted a literature search using different databases such as Embase, Scopus, Web of Sciences, PubMed, Science Direct and Google Scholar until July 2023. We selected search terms based on the objectives of this study. After screening a total of 30 articles were included. RESULTS: The combination of doxorubicin and metformin demonstrated robust anticancer effects, surpassing the outcomes of monotherapy drug treatment. In vitro experiments consistently demonstrated inhibition of cancer cell growth and increased rates of cell death. Animal studies confirmed substantial reductions in tumor growth and improved survival rates, emphasizing the synergistic impact of the combined therapy. The research' discoveries collectively emphasize the capability of the co-treat doxorubicin-metformin as a compelling approach in cancer treatment, highlighting its potential to address medicate resistance and upgrade generally helpful results. CONCLUSION: The findings of this study show that the combined treatment regimen including doxorubicin and metformin has significant promise in fighting cancer. The observed synergistic effects suggest that this combination therapy could be valuable, in a setting. This study highlights the need for clinical research to validate and enhance the application of the doxorubicin metformin regimen.

Static magnetic field reduces cisplatin resistance via increasing apoptosis pathways and genotoxicity in cancer cell lines.

Cisplatin is a chemotherapy drug widely used in cancer treatment. Alongside its clinical benefits, however, it may inflict intolerable toxicity and other adverse effects on healthy tissues. Due to the limitation of administering a high dose of cisplatin as well as cancer drug resistance, it is necessary to utilize new methods optimizing treatment modalities through both higher therapeutic efficacy and reduced administered doses of radiation and drugs. In this study, sensitive (A2780) and resistant (A2780CP) ovarian carcinoma cells underwent treatment with cisplatin + static magnetic field (SMF). First, the levels of genotoxicity after treatment were evaluated by Comet assay. Then, cell cycle analysis and apoptosis assay were conducted by a flow cytometer. Lastly, the expression levels of genes involved in apoptosis and cellular drug uptake were investigated by PCR. After treating different groups of cells for 24, 48, and 96 h, the co-treatment of SMF and cisplatin as a combination managed to increase the amount of DNA damage in both sensitive and resistant cell lines. A considerable increase in mortality of cells was also observed mostly in the form of apoptosis, which was caused by inhibition of the cell cycle. The combination also increased the expression levels of apoptotic genes, namely P53 and P21; however, it did not have much effect on the expression levels of BCL2. Besides, the levels of CTR1 gene expression increased significantly in the groups receiving the aforementioned combination. Our study suggests that the combination of cisplatin + SMF might have clinical potential which needs further investigations through future studies.

Evaluation of the effects of photodynamic therapy consisted of the blue laser and zinc oxide QDs on MDA-MB-231 cancer cells by inhibiting cancer markers and inducing apoptosis.

The increasing number of cancer patients has cast attention on developing new anti-cancer modalities. Photodynamic therapy is a safe anti-cancer approach, which encompasses (1) local administration of a photosensitizer and (2) light irradiation. Zinc oxide (ZnO) quantum dots (QDs) are photosensitizers that can be utilized for this purpose. In the present study, to better appreciate the likely more efficient cytotoxic effect of the combination of ZnO QDs and the visible 470-nm blue light in comparison to the QDs alone, several assays were to be conducted upon breast cancer MDA-MB 231 cells. MTT assay showed that in certain groups the combination displayed higher cytotoxic effects compared to those following QD treatment alone. LDH leakage and lipid peroxidation rates by the combination were significantly higher than treatment with either the blue laser or QDs. Although the combination managed to meaningfully reduce the number of colonies and CAT activity compared to QD treatment, there were no palpable differences between them. Lastly, the combination was able to increase the apoptotic genes, including BAX, TP53, caspase 3, and caspase 9 compared to QD, while, in the case of Bcl-2, an anti-apoptotic gene, none of the groups managed to make any tangible differences on its expression levels. Our findings propose that there may be synergistic effects between the blue laser and QD that can possibly be adopted in anti-cancer therapy in the future. However, further investigations regarding this matter are of the essence.

Evaluation of cytotoxicity impacts of combined methylene blue-mediated photodynamic therapy and intracanal antibiotic medicaments on dental stem cells.

Root canal therapy is a predominant method for treatment of dental pulp and periapical diseases. Conventional methods such as mechanical instrumentations, chemical irrigation and intracanal medicaments pose a huge limitation to root canal disinfection as they kill bacteria and dental stem cells simultaneously. Therefore, much attention has been focused on finding more efficacious antibacterial methods that has no or negligible cytotoxicity for dental stem cells. Herein, we hypothesized that combining antibacterial medicaments with Antimicrobial photodynamic therapy (aPDT) and methylene blue (MB) as a photosensitizer would be effective in reducing death of dental pulp stem cells (DPSCs). To examine this, DPSCs were isolated from third molar teeth through enzymatic digestion. Isolated cells were cultured in αMEM and when reached adequate confluency, were used for further analysis. Cytotoxicity effect of different groups of MB, DAP, MB, LED and their combination on DPSCs was analyzed using MTT assay. DPSCs membrane integrity as a marker of live cells was assessed through measuring lipid peroxidation and lactate dehydrogenase (LDH) release into extracellular space. Results showed that the combination of LED, MB and TAP or aPDT, MB and DAP was more effective in reducing DPSCs death rate compared to TAP and DAP administration alone. Moreover, Malondialdehyde (MDA) and LDH levels were found to be decreased in cells exposed to combination treatment in comparison with single TAP or DAP therapy. Our study shows the promising perspectives of employing combined aPDT, MB and antibiotic medicaments for reduction of dental stem cell death.

Effect of Low-Level Laser Therapy on Differentiation and Proliferation of Human Dental Pulp Stem Cells: A Systematic Review.

Introduction: Considering the positive impact of laser treatment on the proliferation of certain cell types, we opted to perform a systematic review aimed at evaluating the effects of laser therapy and photobiomodulation on the proliferation and differentiation of human dental pulp stem cells (hDPSCs). Methods: We included all research studies examining the impact of laser therapy on hDPSCs, without limitations on publication dates or article languages. The major international databases, including PubMed, ISI Web of Science, and Scopus, were searched from inception to April 2022 by the relevant keywords. Results: In total, 1886 studies were identified in the initial search from the mentioned databases and other sources. Finally, 17 relevant studies were included in the present systematic review after removing duplicates and non-relevant articles. The results indicated the useful effect of low-level laser therapy (LLLT) on the hDPSCs. Conclusion: The findings of this systematic review indicate the useful role of LLLT in cell therapy, proliferation, and differentiation associated with hDPSCs.

Assessing Radiosensitivity: Effects of Acute Ionizing Radiation on Inflammation and Apoptosis in Macrophage Cell Line (RAW 264.7).

Introduction: The responses of biological systems to various types of radiation have multifaceted dimensions. In the field of ionizing radiation, in vitro external gamma radiation therapy has primarily been studied as a model to elucidate the challenges that biological systems face from radiation effects. Exposure of cells/organisms to gamma radiation results in a cascade of ionization events that can cause severe and irreversible biological damage. However, the biological responses and oxidative stress-related mechanisms under acute radiation conditions remain poorly understood in inflammatory systems. The present study aimed to provide a model of the effect of ionizing radiation on macrophages, which play a pivotal role in the mechanisms of inflammation, to assess the impact of radiotherapy as an approach to treating inflammatory diseases. Methods: A macrophage cell line (RAW 264.7) was cultured and exposed to different doses of gamma radiation (4, 6, 8, 10 Gy). Cell viability, apoptosis, cell cycle, migration, nitric oxide (NO) and prostaglandin E2 (PGE2) production, expression of pro-inflammatory and apoptotic genes, and cytokine secretion of macrophages were also evaluated. Results: The results showed that gamma radiation at 4 Gy had a low effect on macrophage characteristics and cytokine secretion patterns. In contrast, higher doses (8 and 10 Gy) increased DNA damage, expression of apoptotic genes, and secretion of NO and PGE2 cytokines. 6 Gy radiation, the maximum radiation dose, showed moderate non-destructive effects and inflammation process modulation. In this study, doses higher than 6 Gy of Gamma radiation caused cell mortality. Conclusion: It appears that 6 Gy of gamma radiation modulates the inflammatory cascade caused by macrophage cells.

Combination of Dental-Capping Agents with Low Level Laser Therapy Promotes Proliferation of Stem Cells from Apical Papilla.

Background: Direct pulp capping is a vital pulp therapy, which stimulates differentiation of stem cells from apical papilla (SCAPs). SCAPs have multipotential capacity to differentiate into types of cells, contributing to the regeneration of tissues. Objective: Considering the promising effects of dental-capping materials, we aim to investigate the effect of dental dressing materials combined with laser therapy on the percentage of SCAP viability and the consequent dental regeneration capacity. Methods: We collected two immature third molar teeth and isolated SCAPs through collagenase type I enzymatic activity. Isolated SCAPs were then cultured with Dulbecco's modified Eagle's medium and α-minimum essential medium enriched with 15% and 10% fetal bovine serum, respectively. After reaching 70-80% confluency, cells were seeded in a 96-well plate and then treated with mineral trioxide aggregate (MTA), enamel matrix derivative (EMD), biodentine, and low level laser therapy (LLLT) alone and in combination for 24, 48, and 168 h. After that, cell survival rate was assessed using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay. Results: We found that combination of MTA, EMD, and LLLT as well as that of biodentine, EMD, and LLLT could lead to significant increase of SCAP viability as compared with other treatment groups. Combination of MTA and biodentine with EMD could also show increased level of SCAP proliferation and viability. However, MTA and biodentine alone reduced SCAP survival rate in all time points. Conclusions: Our conclusion is that LLLT can serve as an enhancer of SCAP proliferation and differentiation rate when added to dental-capping agents such as MTA, EMD, and biodentine. Thus, LLLT combination with effective capping materials will serve as a promising option for dental tissue repair.

Construction a CO2 Incubator for Cell Culture with Capability of Transmitting Microwave Radiation.

Background: The objective of this study was to design and construct a CO2 incubator with nonmetallic walls and to investigate the viability of the cells and microwave irradiance inside this incubator. Methods: Because the walls of conventional incubators are made of metal, this causes scattering, reflection, and absorption of electromagnetic waves. We decided to build a nonmetallic wall incubator to examine cells under microwave radiation. Incubator walls were made using polyvinyl chloride and Plexiglas and then temperature, CO2 pressure, and humidity sensors were placed in it. Atmel® ATmega1284, a low-power CMOS 8-bit microcontroller, collects and analyzes the sensor information, and if the values are less or more than the specified limits, the command to cut off or connect the electric current to the heater or CO2 solenoid valve is sent. Using a fan inside the incubator chamber, temperature and CO2 are uniforms. The temperature of the points where the cell culture plates are placed was measured, and the temperature difference was compared. Ovarian cancer cells (A2780) were cultured in the hand-made and commercial incubators at different times, and cell viability was compared by the MTT method. Microwave radiation in the incubator was also investigated using a spectrum analyzer. The survival of cells after microwave irradiation in the incubator was measured and compared with control cells. Results: The data showed that there was no significant difference in temperature of different points in hand-made incubator and also there was no significant difference between the viability of cells cultured in the hand-made and commercial incubators. The survival of irradiated cells in the incubator was reduced compared to control cells, but this reduction was not significant. Conclusion: This incubator has the ability to maintain cells and study the effects of electromagnetic radiations on the desired cells, which becomes possible by using this device.

Combination of cisplatin treatment and photodynamic therapy attenuates cisplatin-induced cell toxicity in A2780 and A2780-CP cervical cancer cell lines.

Cervical cancer is recognized as a serious worldwide health problem. Despite various achievements for cervical cancer treatment, there are still shortcomings that lead to severe side effects. Combination therapy is fast becoming a key and promising treatment strategy, diminishing chemotherapy-mediated side effects. The objective of this study was to determine the effect of combined cisplatin treatment and photodynamic therapy (PDT) on the cervical cancer recovery. In this study, A2780 and A2780-CP cell lines were cultured in the Dulbecco's modified eagle medium (DMEM) enriched with 10% FBS and 1% antibiotic. Both cell lines were treated with cisplatin, photodynamic light (laser with methylene blue as a photosensitizer agent), and the combination of cisplatin treatment and PDT. Half maximum inhibitory concentration (IC50) was calculated for each treatment by the use of tetrazolium salt assay. Both cell lines were examined for cell membrane lipid peroxidation rate. Our findings showed that combination of cisplatin treatment and photodynamic therapy leads to two-fold decreased cisplatin IC50. Results showed that cisplatin and photodynamic light combination could effectively reduce A2780 and A2780-CP cell viability (p-value < 0.0001). Moreover, combined cisplatin and photodynamic therapy results revealed significantly increased cancer cell membrane destruction through increased lipid peroxidation, resulting in surged MDA content. Our conclusion is that combination of cisplatin and photodynamic therapy can be used as an effective and convenient treatment strategy without considerable side effects.

The effect of cisplatin-low-level laser therapy on cell viability and death of LNCaP prostate cancer cell line.

Prostate cancer, as a common male cancer, is a serious threat to men's health. In spite of extreme developments for increasing survival rate, there are still limitations about common treatment options such as surgical procedures, radiotherapy, and chemotherapy. We hypothesized that combination of two treatments would bring better clinical outcomes. Therefore, the aim of this study was to determine the effect of conjugated cisplatin and low-level laser treatment (LLLT) on the viability of LNCaP prostate cancer cell line. LNCaP cells were harvested in DMEM containing 10% FBS and 1% antibiotic. Confluent cells were treated with different concentrations of cisplatin and different wavelengths of low-level laser (LLL) alone and in combination. The relative IC50 and cell viability was evaluated using MTT assay. Analysis of lipid peroxidation rate was performed using lipid peroxidation assay kit. LDH activity was also carried out on the treated and control cells using LDH cytotoxicity assay kit. Our results showed that combination of cisplatin and LLLT could effectively decrease cisplatin-induced cytotoxicity as well as LNCaP cell viability. Cisplatin-LLLT combination led to a significant increase in the MDA content as the product of membrane lipid peroxidation. Analyzing the LDH activity under the effect of cisplatin-LLL combined treatment showed a remarkable increase in the enzyme activity. We conclude that applying the cisplatin-LLL combination therapy is promising as an effective anti-cancer treatment. This novel combination has a potential to attenuate adverse side effects of earlier monotherapy strategies.

Combination of Dental Capping Agents With LowLevel Laser Therapy Increases the Cell Viability Percent of Stem Cells From Apical Papilla (SCAPs).

Introduction: Dental pulp capping is a technique that is highly applicable in dental restorations. In this technique, a material is directly placed over the exposed pulp tissue, which promotes pulp healing and generates reparative dentin. Herein, we aimed to investigate the combined effect of different pulp capping agents, including mineral trioxide aggregate (MTA), Emdogain (EMD), calcium-enriched mixture (CEM), and low-level laser therapy (LLLT), on enhancing viability and proliferation of stem cells from apical papilla (SCAPs). Methods: SCAPs were isolated from two immature third molar teeth through collagenase type I enzymatic activity. Isolated stem cells were then cultured with DMEM and α-MEM media enriched with 15% and 10% FBS respectively. After reaching 70%-80% confluency, the cells were seeded in a 96-well plate. Cell viability percent was assessed using the MTT assay after treatment with MTA, EMD, CEM and LLLT (λ=630 nm, 5 mW, 4 J/cm2 ) alone and in combination for 24, 48 and 168 hours. Results: Combination of MTA, CEM, EMD and LLLT resulted in significantly increased SCAPs viability as compared with other treatment groups. Increased SCAPs proliferation and viability were also observed in groups treated with the combination of MTA and CEM with EMD. However, the SCAPs survival rate in all defined time spans was reduced after treatment with MTA and CEM alone. Conclusion: LLLT can be a stimulator of SCAPs cell viability when applied in combination with dental capping agents such as MTA, EMD and CEM, providing a therapeutic option for stem cell-based dental regeneration.

Evaluation of Biological Activity of Different Wavelengths of Low-Level Laser Therapy on the Cancer Prostate Cell Line Compared With Cisplatin.

Introduction: Cancer is one of the most important problems in the world. Low-level laser therapy (LLLT) has been emerged as a new approach, having both stimulation and inhibition effects on cellular function. The goal of this study was to analyze and compare the different concentrations of cisplatin and wavelengths of laser therapy on the LnCap cell lines. Methods: LnCap cells were cultured and treated with different concentrations of cisplatin (0.1, 0.4, 0.8, 1.2 and 2 µg/mL for 24 hours) and wavelengths of laser therapy (610, 630 and 810 nm) (0.45 J/cm2) separately. The viability of cells was examined by MTT assay and IC50 was also calculated. Furthermore, a combination of cisplatin IC50 (24 hours) and different wavelengths of the laser was examined. Results: The results of this study showed that 2 µg/mL of cisplatin has the most significant reduction effect on the cell viability of the LnCap cell line. Cisplatin decreased the viability of cells in a dose-dependent manner. Moreover, IC50 of cisplatin was 1.24 µg/mL. On the other hand, LLLT with wavelengths of 610, 630 and 810 nm did not show notable biological effects on cell viability. Conclusion: As known, cisplatin has the capability to reduce the viability of LnCap cell lines. However, LLLT cannot be a remarkable option for the treatment of prostate cancer. Therefore, although laser therapy showed praiseful therapeutic activity against some cancer cell lines, in this study the results indicated that defined laser wavelengths had no inhibitory effects against the prostate cancer cell line.

Investigation into the Effect of Photodynamic Therapy and Cisplatin on the Cervical Cancer Cell Line (A2780).

Introduction: Cervical cancer is recognized as one of the major causes of mortality among elderly women. Although there are several different therapeutic worldwide guidelines, many researchers have focused on screening new methodologies and technologies to elevate the efficiency of cervical cancer treatment. The simultaneous use of photodynamic therapy (PDT) along with chemotherapy as cisplatin has achieved good aims in the treatment of cervical cancer. Methods: A2780 cells were treated with cisplatin, photodynamic progress (laser with methylene blue as a photosensitizer compound) and a combination of cisplatin and PDT. The lithic effect of the laser, methylene blue and their combination and the IC50 value of cisplatin were calculated for each group. The amount of malondialdehyde (MDA) as membrane lipid peroxidation product and released lactate dehydrogenase was measured in the medium. The toxicity of each agent was evaluated by the MTT technique. Results: The results show that a combination of PDT and chemotherapeutic agent cisplatin caused a twofold decrease in viable cervical cancer cells compared to each therapeutic progress. The combination of both laser therapy and cisplatin enhanced cancer cell membrane disruption by increased membrane lipid peroxidation and apoptotic enzyme activation by the elevation of lactate dehydrogenase activity. Conclusion: The results indicated that cisplatin combined with PDT had a greater therapeutic effect on A2780 as a cervical cancer cell line. Therefore, PDT in combination with chemotherapy enhances the effectiveness of chemotherapeutic agents by the disruption of the cancer cell membrane and switching the apoptosis progress with less adverse effects.

Combination of static magnetic field and cisplatin in order to reduce drug resistance in cancer cell lines.

Purpose: In this study, the effects of different intensities of Static Magnetic Fields (SMFs) (10, 15 and 25 mT) and different concentrations of cisplatin drug were investigated on the viability percent and IC50 of the A2780 and A2780-CP cell lines at 24, 48 and 96 h to show useful potential of SMF as a physical agent to enhance the effectiveness of common therapeutic approaches and decrease of drug resistance to cisplatin anticancer drug. Materials and methods: Magnetic field exposure was performed using a locally designed generator. The cell viability percent, IC50 and cisplatin uptake in treated cells were evaluated by MTT assay and inductively coupled plasma (ICP), respectively. Results: Increasing of concentration and time of cisplatin drug showed a noticeable decrease in viability percent in sensitive and resistant cell lines compared with control group. These decreases were more significant in resistant cells compared with sensitive cells. The obtained IC50 values for resistant were greater than the values obtained for A2780 cells. ICP analysis demonstrated an increased uptake of cisplatin after treatment for 48 and 96 h relative to untreated groups in both resistant and sensitive cells. Conclusion: Results showed that A2780 cells were more sensitive to cisplatin than A2780-CP. Studies have shown that SMF can increase the effect of cisplatin on cell viability percent and decrease the resistance of A2780-CP cells by producing large, verruca shaped structures at the surface of the cell membrane.

Simultaneous application of cisplatin and static magnetic field enhances oxidative stress in HeLa cell line.

In this study, we reported the effects of simultaneous application of static magnetic field (SMF) and cisplatin as an anticancer drug on the oxidative stress in human cervical cancer (HeLa) cell line and normal skin fibroblast cells (Hu02). The cells were exposed to different SMF intensities (7, 10, and 15 mT) for 24 and 48 h. IC50 concentrations of cisplatin were obtained by MTT assay. The cytotoxic effects of combined treatment were studied by measuring the intracellular reactive oxygen species content using flow cytometric method and estimation of membrane lipid peroxidation by spectrophotometry. Statistical analysis was assessed using one-way repeated measures analysis of variance (ANOVA) followed by Tukey's test. Based on the obtained results, the highest and lowest death rate, respectively, in HeLa and Hu02 cell lines was observed at the intensity of 10 mT. Also, we found that membrane lipid peroxidation in cancer cells is higher than that of normal counterparts. SMF potently sensitized human cervical cancer cells to cisplatin through reactive oxygen species (ROS) accumulation while it had small effects on normal cells. The combination of both treatments for 48 h led to a marked decrease in the viability percentage of HeLa cells by about 89% compared to untreated cells. This study suggests that conjugation of both physical and chemical treatments could increase the oxidative stress in HeLa cell line and among three optional intensities of SMF, the intensity of 10 mT led to the higher damage to cancer cells in lower doses of drug.

Investigation of gene expressions in differentiated cell derived bone marrow stem cells during bone morphogenetic protein-4 treatments with Fourier transform infrared spectroscopy.

A model was set up to predict the differentiation patterns based on the data extracted from FTIR spectroscopy. For this reason, bone marrow stem cells (BMSCs) were differentiated to primordial germ cells (PGCs). Changes in cellular macromolecules in the time of 0, 24, 48, 72, and 96h of differentiation, as different steps of the differentiation procedure were investigated by using FTIR spectroscopy. Also, the expression of pluripotency (Oct-4, Nanog and c-Myc) and specific genes (Mvh, Stella and Fragilis) were investigated by real-time PCR. However, the expression of genes in five steps of differentiation was predicted by FTIR spectroscopy. FTIR spectra showed changes in the template of band intensities at different differentiation steps. There are increasing changes in the stepwise differentiation procedure for the ratio area of CH2, which is symmetric to CH2 asymmetric stretching. An ensemble of expert methods, including regression tree (RT), boosting algorithm (BA), and generalized regression neural network (GRNN), was the best method to predict the gene expression by FTIR spectroscopy. In conclusion, the model was able to distinguish the pattern of different steps from cell differentiation by using some useful features extracted from FTIR spectra.

Investigation on the effect of static magnetic field up to 30 mT on viability percent, proliferation rate and IC50 of HeLa and fibroblast cells.

We have investigated the effects of static magnetic field (SMF) on the viability of the human cervical cancer (HeLa) cell line and fibroblast cells. The cells were cultured in DMEM medium and treated several times (24, 48,72 and 96 h) and at several intensities (5, 10, 20 and 30 mT) of magnetic field (MF). The cytotoxicity and cell viability percent in treated cells were performed using MTT assay by evaluating mitochondrial dehydrogenase activity. The MF ability on inducing cell death or inhibiting biochemical function was reported as cell death percent. The results showed that the increase of MF intensity and the time that cells were exposed to this treatment increased sharply cell death percent and proliferation rate in HeLa cell compare to fibroblast cells. Our data suggest that SMF biological effects on cell death were different in our selected targets. Cell type and time of exposure have been therefore found to be significant factors. These findings could be used to improve new effective method using SMF in conjunction with the common therapeutic approaches.