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. 2017 Nov 20;51(2):e12417. doi: 10.1111/cpr.12417

Low level laser therapy induces increased viability and proliferation in isolated cancer cells

C Kara 1,✉, H Selamet 1, C Gökmenoğlu 1, N Kara 2
PMCID: PMC6528928  PMID: 29160001

Abstract

Objectives

Low level laser therapy (LLLT), which stimulates natural biological processes in the application region, is frequently used in dental treatments. The aim of our study was to evaluate the effects of LLLT which could activate precancerous cells or increase existing cancerous tissue in case of clinically undetectable situations.

Materials and methods

Saos‐2 osteoblast‐like osteosarcoma cells and A549 human lung carcinoma cells were used. Twenty‐four hours after preparation of cell culture plates, laser irradiation was performed 1, 2 and 3 times according to the test groups using Nd:YAG laser with the power output 0.5, 1, 2 and 3 W. Cell proliferation analysis was performed by MTT assay at the 24th hour following the last laser applications.

Results

Generally, it was observed that the proliferation rates increased as the number of applications increased, when compared to the controls, especially in those cases in which the irradiation was performed 2 or 3 times more.

Conclusion

The findings of this study have led to the conclusion that LLLT increases cancer cell proliferation, depending on the power output level of the laser and the number of applications. In addition to the proliferation and mitotic activity of the cancer tissue cells, we concluded that LLLT, which is frequently used in dental practice, could activate precancerous cells or increase existing cancerous tissue.

Keywords: low level laser therapy, lung carcinoma, Nd: YAG laser, osteosarcoma

1. INTRODUCTION

Cancer is a disease characterized by the uncontrolled proliferation of a group of cells within the body, much faster than that of the surrounding normal cells. Today, cancer is a serious health problem, with the emergence of antagonists due to mortality and morbidity and an increasing frequency in many parts of the world.1 According to the World Health Organization, the number of cancer cases seen in 2008 was 12.7 million, and this figure will reach 21 million by 2030.2 Several factors play roles in the aetiology of cancer, with 85% of cancer cases being caused by environmental factors and 15% due to genetic factors.3 The main environmental factors that cause cancer include ionizing radiation, ultraviolet rays, smoking, air pollution, alcohol, nutrition and diet, chemical substances and microorganisms.4

Some basic rules must be violated for the development of a cancerous cell.5 First, the division of cells normally occurs only when they receive the correct signal. In order to violate this rule, when the cell is stimulated by an agent such as a hormone or growth factor, it must overcome the normal process to make the cell division permanent. Second, the “safety brakes” that prevent cells from developing abnormally or undergoing excessive cell division must be eliminated. These brakes are controlled by two main genes: RB1 and TP53. When these genes are mutated, they prevent apoptosis, thereby allowing the formation of a tumourous mass. The realization of these changes is sufficient for cells to become cancerous. However, at the molecular level, this is not a simple process. In fact, a cancer cell is able to operate all of these changes in a coordinated manner. Thus, genetic weaknesses and environmental changes can both play major roles in this process.6

Lasers, especially neodymium‐doped yttrium aluminium garnet lasers (Nd:YAG), have been used for a wide range of dental applications, including endodontics,7 periodontics,8 preventive dentistry,9 and oral surgery.10 Despite the common use of these dental lasers, there is another type of laser, a low level laser, which does not cut or ablate the tissues. The basic principle of low level laser therapy (LLLT) is based on biostimulation or the biomodulation effect, meaning that irradiation at a specific wavelength is able to alter the cellular behaviour.11 The mechanism of LLLT is based directly on the application of biostimulatory light energy to the cells.12 The cellular photoreceptors absorb the LLLT light, and can transfer it to the mitochondria to produce ATP. With the increase in the vasodilatation via ATP synthesis, the use of oxygen is increased, and the activity of the cytoplasmic enzymes with the nucleic acids stimulates cell mitosis.13

Low level laser therapy, which stimulates natural biological processes in the application region, is frequently used in many different dental treatments, including the healing of chronic/acute wounds and shortening the recovery process of operative areas with minimal pain.14 In addition to these positive results, LLLT, which has been known to cause cell mitosis, may induce negative results by proliferating cancer cells. The aim of our study was to evaluate the effects of LLLT, which could activate precancerous cells or increase existing cancerous tissue (in cases of clinically undetectable situations), on osteoblast‐like osteosarcoma persistent cells and lung cancer cells cultures in vitro.

2. MATERIALS AND METHODS

All of the experimental procedures were submitted to and approved by the Clinical Research Ethics Committee of Ordu University (no: 2016/85). The experimental part of the study was carried out in the Atigencell‐Trabzon Cell Culture Laboratory.

2.1. Cell culture

This study used commercially obtained human Saos‐2 osteoblast‐like cells (ATCC85‐HTB) and A549 human lung carcinoma cells. The cells were grown in T75 tissue culture flasks (Nest Biotech, China) using minimum essential medium alpha (Lonza, USA) supplemented with 10% foetal bovine serum (Lonza, USA), antibiotics (penicillin and streptomycin) and antimycotics (Fungizone). Incubation was performed at a constant temperature (MCO‐17 AI; Sanyo, Japan) with 5% CO2 to provide a 95% humidified air mixture at 37°C. The cell culture media were subjected to pH monitoring with daily bacterial and fungal contamination, and the nutrients were renewed every 2 days. When the cancer cells reached confluence, the cell monolayer was washed with Ca and Mg‐free phosphate‐buffered saline followed by trypsin (Lonza, USA) to prepare a single cell suspension. After counting the cells using a Thoma cell counting chamber under an inverted microscope, the cell concentration was adjusted to 1 × 105 cells/mL.

2.2. Determination of the total cell count using a haemocytometer

The intercellular junctions of the Saos‐2 and lung cancer cells were removed, and the cells were detached from the sterile culture dishes using 0.25% trypsin‐EDTA (Lonza, USA). After centrifugation (1500 rpm for 5 minutes), the liquid remaining in the upper part of the tubes was discarded with a Pasteur pipette. The cells collected in the bottom of the tube were resuspended in 1 mL of fresh medium, and 10 μL of the suspension was mixed with 10 μL of trypan blue (Celis, 1998). This mixture was counted by spreading it on a Thoma slide. The total number of cells per millilitre of suspension was found by using the Louis and Siegel formula.15

2.3. Laser irradiation procedure

For this study, 12 plates with 96 wells each were used, and the cell culture was prepared by dividing it into 6 each of Saos‐2 plates and A549 plates. The different cell culture plates were further divided into 3 groups according to the LLLT application periods (group I: one LLLT application, group II: two LLLT applications, and group III: three LLLT applications). Two plates in each group were also divided into control and laser doses (first plate: 0.5‐watt LLLT, 1‐watt LLLT, control; second plate: 2‐watt LLLT, 3‐watt LLLT, control). The cells were seeded at an initial density of 5 × 104 cells/cm2 in all of the wells of the plates.

For the laser applications, a free‐running pulsed‐wave Nd:YAG laser with a wavelength of 1064 nm under air cooling (SmartFile; DEKA, Calenzano, Italy) with a phototherapy probe was used under the following irradiation parameters: power output 0.5‐1‐2‐3 W, energy 100 mJ, frequency 5‐10‐20‐30 Hz, continuous wave mode, time 0.5 minutes, and 1 cm distance from the culture media. The non‐irradiated control cells were subjected to room light for the same period of time and maintained outside the incubator under the same conditions as the laser‐irradiated cells. The same researcher performed all of the LLLT applications to prevent inter‐operator variations. A schematic representation of the 96‐well plates prepared for the cell proliferation and LLLT applications is shown in Figure 1.

Figure 1.

Figure 1

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The schematic representation of the 96‐well plates for LLLT applications

2.4. Cell proliferation/viability assay

A methylthiazole diphenyl tetrazolium (MTT) test, based on the determination of the metabolic activity, was used to assess the cell proliferation. MTT, at a concentration of 0.5 mg/mL, was added to all of the wells. Following 3 h of incubation at 37°C and 5% CO2, the contents were replaced with dimethyl sulphoxide (DMSO) to extract the formazan crystals from inside the cells for 15 minutes at room temperature. Subsequently, 100 mL of a purple coloured sample solution was transferred from each well into a new 96‐well plate, and the optical density (OD) was read using a microplate reader (Sunrise; Tecan, USA) at 570 nm. Since the amount of colour produced is directly proportional to the number of viable (metabolically active) cells, the relative numbers of the adhered live cells on the discs could therefore be determined based on the optical absorbance of the sample. The mean values at the 96‐h post‐seeding time point were recorded and tabulated in a graph.

2.5. Statistical analysis

The statistical analyses were performed by using the Statistical Package for the Social Sciences (SPSS 11.5 for Windows; SPSS Inc., Chicago, IL, USA) software. When analysing the data, a two‐way ANOVA was used. P ≤ .05 were accepted as statistically significant.

3. RESULTS

In this study, the cell proliferation values were assessed via MTT assay as a result of biostimulation applied to the cancer cells at different powers. Generally, it was seen that the cell proliferation rates were higher in the treatment groups than in the control groups. However, a lower cell proliferation was detected in those cells irradiated with 3 watts of power. It was observed that the proliferation rates increased as the number of applications increased, when compared to the controls, especially in those cases in which the irradiation was performed 2 or 3 times more. In addition, it was observed that there was less proliferation in the samples irradiated 3 times with 3 watts of power.

The statistical data obtained as a result of the A549 lung cancer cell proliferation tests are presented in Table 1 and Figure 2. When the proliferation rates in the test and control groups for the A549 lung cancer cells were compared in terms of the laser irradiation power level, the most proliferation was observed in those cells treated with 1 and 2 watts. Although a statistically significant increase was observed in the proliferation levels, particularly at 0.5 watts, the increase in the power levels at 1 and 2 watts was greater than at the 0.5‐watt power level. When the proliferation rates in the test and control groups for the A549 lung cancer cells were compared in terms of the number of laser irradiation applications, the most proliferation was observed in those cells with 2 and 3 applications. Moreover, the proliferation levels were increased statistically when compared to the control group in the case of 1 application, but the increases in 2 and 3 applications were even greater. In general, the highest proliferation value was obtained with 1 watt of power for 2 applications, and the lowest was with 3 watts of power for 3 applications.

Table 1.

Cell proliferation rates of test and control groups of A549 lung cancer cells at OD 570 nm on day 4

Laser applications
1 2 3 Total
Power Output Control 0.746 ± 0.024 ab 0.736 ± 0.027 ab 0.741 ± 0.027 ab 0.741 ± 0.026 A
0.5 Watt 0.757 ± 0.026 a 0.796 ± 0.025 cd 0.796 ± 0.025 cd 0.780 ± 0.032 B
1 Watt 0.759 ± 0.027 ae 0.815 ± 0.030 c 0.806 ± 0.038 cd 0.793 ± 0.040 C
2 Watt 0.754 ± 0.029 ab 0.801 ± 0.026 cd 0.814 ± 0.051 cd 0.790 ± 0.044 BC
3 Watt 0.708 ± 0.026 b 0.692 ± 0.022 f 0.685 ± 0.039 f 0.695 ± 0.034 D
Total 0.745 ± 0.028 A 0.767 ± 0.048 B 0.764 ± 0.057 B
Variation sources
Power output (PO) Laser applications (LA) PO*LA
P‐value <.001 <.001 <.001
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Values are expressed as a group mean ± SD. Bold values show maximum and minimum cell proliferation rates.

Figure 2.

Figure 2

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The graph of cell proliferation rates of test and control groups of A549 lung cancer cells at day 4 OD 570 nm

The statistical data obtained as a result of the human osteoblast‐like Saos‐2 cell proliferation tests are presented in Table 2 and Figure 3. Although a statistically significant increase was observed in the proliferation levels, especially with 0.5 and 2 watts of power, the increase in the 1 watt power level was found to be greater than in the 0.5 and 2 watt power levels. In general, the highest proliferation value was obtained from the cell samples irradiated at 1 watt, with the lowest at 3 watts. When the proliferation rates in the test and control groups for the Saos‐2 cells were compared in terms of the number of laser irradiation applications, the most proliferation was observed in those cells that had been administered 3 applications. Moreover, in one application, there was a statistically significant increase in the proliferation levels when compared to the control group, but the increases in 2 and 3 applications were greater than in 1 application. In general, the highest proliferation was obtained with 3 applications at 1 watt of power, with the lowest in 3 applications at 3 watts of power.

Table 2.

Cell proliferation rates of test and control groups of human osteoblast‐like cells of SaOs‐2 at OD 570 nm on day 4

Laser applications
1 2 3 Total
Power Output Control 0.398 ± 0.037 a 0.392± 0.043 a 0.400 ± 0.055 ab 0.397 ± 0.045 A
0.5 Watt 0.416 ± 0.017 a‐d 0.436 ± 0.026 b‐e 0.458 ± 0.034 e 0.436 ± 0.031 B
1 Watt 0.416 ± 0.025 a‐d 0.455 ± 0.036 e 0.466 ± 0.049 e 0.446 ± 0.044 B
2 Watt 0.409 ± 0.030 abd 0.450 ± 0.042 ce 0.444 ± 0.046 cde 0.434 ± 0.043 B
3 Watt 0.341 ± 0.038 f 0.323 ± 0.045fg 0.291 ± 0.039 g 0.318 ± 0.045 C
Genel 0.396 ± 0.040 A 0.408 ± 0.060 B 0.410 ± 0.075 B
Variation sources
Power output (PO) Laser applications (LA) PO*LA
P‐value <.001 <.001 <.001
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Values are expressed as a group mean ± SD. Bold values show maximum and minimum cell proliferation rates.

Figure 3.

Figure 3

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The graph of cell proliferation rates of test and control groups of human osteoblast‐like cells of SaOs‐2 at day 4 OD 570 nm

4. DISCUSSION

In this study, we hypothesized that LLLT, which is frequently used nowadays, could activate precancerous cells or increase existing cancerous tissue by increasing the proliferation and mitotic activity of cancer tissue cells. We also wanted to show that LLLT, which is emphasized as an advantage and benefit in most studies, should be used in a more controlled and conscientious way.

Cancer occurs as a result of the mutation or abnormal activation of genes controlling cell mitosis. Increased proliferation and decreased apoptosis are caused by the loss of cell cycle control.16 Many oncogenes (fibroblast growth factors, epithelial growth factor receptors, etc.) that function in the regulation of cell growth and the transmission of nuclear signals from the cell membrane undergo changes in cancer.17

For tumours larger than 1 mm in size, there is a need for new angiogenesis. This new formation is mediated by the induction of tumour cell‐mediated or angiogenic proteins (eg, vascular endothelial growth factors and fibroblastic growth factors). In head and neck cancers, such angiogenic proteins have been identified and are thought to be responsible for the angiogenesis associated with the development of these tumours. The regulation of certain environmental and lifestyle factors that can be controlled may reduce the occurrence of some types of cancer.18

In the fields of medicine and dentistry, in addition to the standard treatments for diseases, the use of different devices has become commonplace in accordance with the developments in technology and research. Lasers have been investigated for this purpose, and it is believed that LLLT has the potential to stimulate normal cell functions. LLLT has been reported to increase ATP, accelerate mitosis, improve tissue repair, stimulate bone repair, normalize collagen and elastic fibril accumulation in tissue repair, stabilize fibroblast production, increase peripheral blood flow and improve anti‐inflammatory activity.19 Although it has been shown to stimulate cell proliferation and collagen synthesis, it is not known exactly how these effects could change clinical outcomes. Overall, it has been reported that LLLT increases DNA synthesis, the amount of collagen and procollagen, and the rate of proliferation. In dentistry, LLLT is frequently used to treat oedema and inflammation, acute‐chronic pain, herpes simplex, dentinal tooth sensitivity, neuralgia and inferior alveolar nerve injuries, and to accelerate tissue healing, so it had been subjected to many research studies.20 However, it remains unclear whether the biochemical reactions that occur as a result of LLLT and any side effects of LLLT are still present.

In a study evaluating gingival healing following LLLT in patients undergoing gingivectomies, better improvement was seen in the laser‐treated cases.21 Two animal studies in which wound healing was evaluated clinically and histopathologically after vestibuloplasty and free gingival graft operations showed that LLLT provided better and faster wound healing and increased epithelization. In addition, Üşümez et al22 demonstrated that LLLT stimulated the platelet‐derived growth factor and basic fibroblast growth factor (bFGF) responsible for cell proliferation and fibroblast growth, thereby accelerating the wound healing process. Other animal studies have shown that LLLT was effective in bone healing by affecting calcium migration during new bone formation, and that the bone maturation was faster.23

In one in vitro study, the researchers found that LLLT had a prominent proliferation effect on human gingival fibroblast cells, but the duration of this effect was limited.24 These findings show that repeated applications are necessary to achieve a positive laser effect in clinical practice. In our study, it was seen that the cell proliferation rates were higher in the laser‐treated cultures than in the control group. When we looked at the cell proliferation levels in terms of application periods, we found that the proliferation rates increased with an increasing application frequency when compared to the controls, especially for 2 and 3 applications.

In another in vitro study in which the effects of LLLT on the proliferation and differentiation of human osteoblast cells were investigated, a 31%‐58% survival rate was found in the laser‐treated cells, with an increase in the ALP activation and osteopontin and bone sialoprotein expression.25 Saygun et al26 showed that in vitro LLLT stimulated the proliferation of osteoblast cells and the release of bFGF, insulin‐like growth factor 1, and insulin‐like growth factor binding protein 3 from these cells. In a study of the effects of LLLT on the proliferation of normal osteoblast cells and malignant osteosarcoma cells, the osteoblast and osteosarcoma cell proliferation significantly increased.27 However, the alkaline phosphatase (ALP) activity in osteosarcoma cells did not change independently of the laser wavelength and intensity. Based on the results of this study, it was concluded that each cell had different responses to different wavelengths and dose combinations.

The effects of LLLT on cancer tissues were also investigated. In one in vitro study of LLLT in which the time and frequency of treatment and the effect of the wavelength were evaluated on the proliferation of human epithelial type 2 (HEp‐2) cells, the same energy density was used at 2 different wavelengths (685 nm and 830 nm) with a diode laser. According to the results, the time, wavelength, and treatment of the HEp‐2 cells affected the proliferation process.28 In addition, Kreisler et al29 found that the proliferation rate of human laryngeal carcinoma cells was higher in their LLLT group. Moreover, in studies evaluating the proliferation effects of LLLT on oral carcinoma cells,30 human breast cancer, melanoma and breast epithelial cells,31 and lung cancer stem cells,32 the result was that the laser treatment had a proliferative positive biomodulatory effect, which was affected by the wavelength.

Another study evaluating the effects of LLLT on melanoma cells (B16F10) resulted in the conclusion that LLLT should be avoided in melanoma cells,33 since the LLLT significantly increased the growth of a melanoma tumour.

In contrast to these studies, LLLT was not found to induce the proliferation of tumour cells in a study in which it was evaluated for cell proliferation, cell cycle distribution and the effects on apoptosis in a human oral carcinoma cell line (SCC‐25).34 Likewise, in our study, although the cell proliferation levels were statistically increased in the LLLT‐treated cell cultures at all of the power values, the increase in the 1 watt power level was found to be greater than in the 0.5 and 2‐watt power levels, with the lowest in the 3‐watt samples. In addition, the most proliferation was observed in the cells with 2 and 3 applications. In general, the highest proliferation value was obtained with 2 applications at 1 watt of power, and the lowest was with 3 applications at 3 watts of power.

The findings of this study have led to the conclusion that LLLT increases cancer cell proliferation, depending on the power output level of the laser and the number of applications. In addition to the proliferation and mitotic activity of the cancer tissue cells, we concluded that LLLT, which is frequently used in dental practice, could activate precancerous cells or increase existing cancerous tissue.

CONFLICT OF INTEREST

The authors declare no conflict(s) of interest.

ACKNOWLEDGEMENTS

The authors would like to acknowledge the statistical assistance of Prof. Dr. Soner ÇANKAYA in the statistical analyses of this manuscript.

Kara C, Selamet H, Gökmenoğlu C, Kara N. Low level laser therapy induces increased viability and proliferation in isolated cancer cells. Cell Prolif. 2018;51:e12417 10.1111/cpr.12417

Funding information

The study was supported by Ordu University Scientific Research Project Unit.

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