Investigation of the Anti-Cancer of Photodynamic Therapy Effects by Using the Novel Schiff-Base Ligand Complex on Human Breast Cancer Cell Line

doi:10.21203/rs.3.rs-4345121/v1

Chemotherapy plays a role in many cancer therapies, including breast cancer, but due to its significant side effects, alternate treatment approaches have been investigated. One such alternative is Photodynamic Therapy (PDT), which employs a combination of oxygen, a photosensitizer (PS), and light of a specific wavelength. Transition metal complexes and SBL have gained interest in PDT. In this study aimed to assess the potential antitumor activity and underlying mechanism of a newly synthesized Schiff Base Ligand (SBL)-mediated PDT on MCF-7 cells, comparing its efficacy to cisplatin. We synthesized and characterized two novel Pd-conjugated SBL compounds (complex-1 and 2). Following the treatment of MCF-7 cells with these compounds, a Light-Emitting Diode (LED) was utilized to deliver a light dose of 14.8 J/cm². In MCF-7 cells, we also looked at cytotoxicity, cell death rates, and ROS levels. Results indicated a significant increase in cytotoxicity and ROS levels in the group treated with complex-1 mediated PDT. The apoptotic and necrotic cell death also rose significantly. In conclusion, our study suggests that the complex-1 compound may serve as a promising candidate for anticancer agents in PDT for MCF-7 cells. In contrast, complex-2 mediated PDT did not demonstrate any observable anticancer activity.

MCF-7

anticancer

photodynamic therapy

reactive oxygen species

schiff base

Breast cancer stands as the second most common cancer globally, surpassed only by lung cancer. Characterized by its significant incidence and mortality rates, breast cancer predominantly affects women. Various factors, including early menopause, obesity, contraceptive use, genetic predispositions, and environmental elements, have been identified as increasing the risk of breast cancer. Indeed, in 2018 alone, over 2.1 million women were diagnosed with new cases of the disease, and 626,679 deaths were attributed to breast cancer (Waks and Winer 2019; Harbeck et al. 2019). Over the past half-century, numerous innovative treatment modalities, such as immunotherapy and personalized cancer therapy, have been developed in the fight against cancer. Yet, conventional chemotherapy still remains a significant treatment modality (Kiyotani et al. 2021; Ignatiadis and Sotiriou 2013). Despite its effectiveness, chemotherapy is associated with serious side effects, including neutropenia, infection, nephrotoxicity, cardiotoxicity, and neurotoxicity (Xu et al. 2018). These adverse effects underscore the urgent need for alternative treatments that operate on different mechanisms.

Photodynamic Therapy (PDT) has emerged as a clinically approved, non-invasive treatment alternative. The process of PDT involves three core components: photosensitizer (PS), oxygen, and light. Typically, the PS is in a low energy level or single state. Upon absorbing photon energy from light, the PS transitions from this single state (S0) to an excited single state (S1), and subsequently to an excited triplet state. Two types of reactions occur at this stage: the Type 1 reaction, where the PS electrons transfer to the substrates to form ROS, and the Type 2 reaction, where the PS transfers energy to molecular oxygen, thereby creating singlet oxygen (Kwiatkowskia et al. 2018; Dolmans et al. 2023). These reactions trigger a series of molecular responses, including cell proliferation, cell death, and increased reactive oxygen species (ROS) (Castano et al. 2006; Santos et al. 2019). Despite extensive exploration into various PS in the application of PDT to breast cancer treatment, no study has, to our knowledge, examined the potential of newly designed Palladium (Pd)-conjugated Schiff Base Ligand (SBL) compounds. Consequently, the present study aims to synthesize these novel compounds and determine their structures using spectrochemical methods. We also intend to examine cytotoxicity, ROS formation, caspase activity, and cell death to determine these agents' anticancer activity on breast cancer cell line (MCF-7) and to elucidate the underlying mechanisms.

SBL compounds are known for their antifungal, antibacterial, antiproliferative, anti-inflammatory, and antiviral properties (Bayeh et al. 2020; Zhao et al. 2018). Furthermore, certain SBL derivatives have demonstrated superior anticancer effects compared to cisplatin, a common chemotherapeutic agent used in melanoma and ovarian cancer treatment (Parveen et al. 2020; Raja et al. 2012). The possibility of conjugating SBL with metals such as zinc, palladium, ruthenium, and platinum has been shown to enhance its bioactivity (Li et al. 2017). Specifically, palladium complexes have been suggested to exhibit considerable anti-tumor activity in cancer cells, with fewer side effects compared to cisplatin (Czarnomysy et al. 2021; Tanaka et al. 2013). This promising avenue for breast cancer treatment motivates our current investigation into the potential of novel Pd-conjugated SBL compounds in PDT.

Synthesis Procedure of Phosphine Ligan

For the synthesis of L1; 10 mL of methanol was added to a 50 mL round bottom flask, 2 (diphenylphosphino)benzaldehyde (200 mg, 0.69 mmol, 1 equiv.) and 4-tert-butylbenzoic hydrazide (132 mg, 0.69 mmol, 1 equiv.) were added and allowed to stir at 60 o C for 12 hours. The progress of the reaction was monitored by TLC and at the end of the reaction the mixture was transferred to a 50 mL beaker and allowed to evaporate. After evaporation of the solvent, the resulting cream-colored solid was used directly (210 mg, 0.45 mmol, 65%). Elemental Analysis: Calculated (%) C 30 H 29 N 2 OP: C, 77.57; H, 6.29; N, 6.03: C, 77.59; H, 6.31; N, 6.01.

The synthesis of L2 followed the same procedure as L1, but instead of 4-tert butylbenzoic hydrazide, 4-fluorobenzoic hydrazide was used (185 mg, 0.43 mmol, 63%). Elemental Analysis: Calculated (%) C 26 H 20 FN 2 OP: C, 73.23; H, 4.73; N, 6.57: C, 73.26; H, 4.71; N, 6.55.

The synthesis scheme of two phosphine ligands is given in Fig. 1.

Synthesis of Palladium Complexes

In the synthesis of the complex 1, a solution of palladium(II) chloride (38 mg, 0.22 mmol, 1 equiv.) dissolved in 10 mL acetonitrile was added dropwise to a 10 mL acetonitrile solution of the L1 ligand (100 mg, 0.22 mmol, 1 equiv.) in a 50 mL beaker. The mixture was allowed to stir at 70 o C for 24 hours. At the end of the reaction, the solution was filtered and allowed to evaporate in a 50 mL beaker. After 5 days, bright orange crystals were collected (96 mg, 0.15 mmol, 69%). The reaction equation for the complex syntheses is given in Fig. 2. Elemental Analysis: Calculated (%) C 30 H 29 N 2 OCl 2 PPd: C, 56.14; H, 4.55; N, 4.36: C, 56.18; H, 4.57; N, 4.33. 1 H NMR (400.2 MHz, DMSO-d 6 ): δ (ppm) 8.80 (d, J = 3.6 Hz, 1H), 8.16–8.06 (m, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.83 (t, J = 7.6 Hz, 1H), 7.74–7.61 (m, 6H), 7.59–7.53 (m, 3H), 7.46 (dd, J = 15.8, 9.4 Hz, 3H), 6.76 (s, 2H), 1.31 (s, 9H). 13 C NMR (101.6 MHz, DMSO-d 6 ): δ (ppm) 173.74, 154.04, 150.78, 137.18, 136.63, 136.44, 134.61, 133.77, 133.66, 133.39, 132.11, 129.18, 129.06, 128.55, 128.23, 127.62, 125.13, 118.01, 117.48, 39.59, 34.66, 30.98. 31 P NMR (162.0 MHz, DMSO-d 6 ): δ (ppm) 31.26 (1P).

In the synthesis of the complex 2, L2 ligand (100 mg, 0.23 mmol, 1 equiv.) was used instead of L1 ligand and the same procedure was repeated (85 mg, 0.15 mmol, 59%) (Figure S1, S2 and S3). Elemental Analysis: Calculated (%) C 26 H 19 N 2 OClFPPd: C, 55.05; H, 3.38; N, 4.94: C, 55.09; H, 3.43; N, 4.97. 1 H NMR (400.2 MHz, DMSO-d 6 ): δ (ppm) 8.79 (d, J = 4.2 Hz, 1H), 8.14–8.02 (m, 3H), 7.83 (t, J = 7.6 Hz, 1H), 7.68 (ddd, J = 15.3, 10.4, 6.5 Hz, 7H), 7.57 (td, J = 7.5, 2.7 Hz, 4H), 7.46 (dd, J = 10.5, 7.9 Hz, 1H), 7.28 (t, J = 8.8 Hz, 2H). 13 C NMR (101.6 MHz, DMSO-d 6 ): δ (ppm) 172.83, 165.17, 162.70, 151.13, 137.16, 136.54, 134.62, 133.79, 133.67, 132.16, 131.16, 129.19, 129.07, 128.18, 127.57, 118.09, 117.56, 115.43, 39.60. 31 P NMR (162.0 MHz, DMSO-d 6 ): δ (ppm) 31.43 (1P) (Figure S4, S5 and S6).

Cell Culture

The human breast cancer (MCF-7) cell line (HTB-22. Manassas. VA. USA) was used in the present study. MCF-7 cells were obtained from the American Type Culture Collection (ATCC). The cells were cultured with 10% Fetal Bovine Serum (FBS), 1 ml 1% Penicillin-Streptomycin, 1 ml 1% Amphotericin, 1.5 ml L-Glutamine (Biowest), and RPMI-1640 medium without Phenol Red (Gibco, Catalog No: 11835030). The cells were then incubated at 37°C in a humidified incubator that contained 5% CO₂.

Dark and PDT Protocol

A stock solution of compounds was prepared in 5% Dimethyl Sulfoxide (DMSO; Sigma Aldrich) and diluted in the medium at determined concentrations such that the DMSO ratio was 0.01% with no effect on cell viability [31]. Cisplatin (Cayman, San Diego, CA, USA) was used as the positive control. MCF-7 cells were incubated with agents for 72 hours in the dark protocol. However, in the PDT protocol, MCF-7 cells were exposed to 14.8 J/cm² a Light-Emitting Diode (LED) light source after incubation with agents for 12 hours. Then MCF-7 cell line were incubated at 37°C in 5% CO₂ until 72 hours.

The LED light source used in the study had an output power of 100 Watts in the spectral range of 400–700 nanometers. The LED light source in the present study was selected in line with the absorption spectrum of PS. When the LED light source was on, the ambient temperature was 37°C. The light intensity of the LED light source used in the present study was measured as 112 klux with a light meter (Cem DT-1308). The light intensity and duration were 900 seconds compared to previous studies (Acedo et al. 2014; Gu et al. 2020) and the light dose was calculated to be 14.8 J/cm².

MTT Analysis

MCF-7 cells were inoculated in a 96-well plate at 2X10⁴ cells/well and incubated overnight. Then the culture medium was aspirated and cells were treated at different concentrations (6.25, 12.5, 25, and 50 µM) of cisplatin (positive control), complex-1, and, complex-2 compounds. Only medium was added to the control group. After the PDT protocol, 200 µL of MTT solution (ab112118, Abcam, Cambridge, UK) was added to all groups at 72 hours and incubated at 37°C for 4 hours. The absorbance value was then measured by reading at 570 and 605 nm wavelengths in a microplate reader (Thermo Scientific Multiskan Go).

Measurement of ROS

The 2’,7’-Dichlorofluorescent Diacetate (DCFDA) Kit (Abcam, Catalog No: ab113851) was used to measure intracellular ROS production. MCF-7 cells were inoculated into a 96-well microplate at a rate of 1.5x10⁵ cells/well in 200 µL. MCF-7 cells were treated with 25 µm cisplatin and 25 µm complex-1 compounds after 24 hours of incubation. After the PDT protocol, all groups were washed with DCFDA buffer and 200 µl 20 µM Tert-Butyl Hydroperoxide (TBHP) solution was added to the positive control group and incubated for 6 hours. All groups were then kept in the dark for 45 minutes with 200 µL of 30 µM DCFDA solution. Readings were made in a microplate reader (Thermo Scientific Multiskan Go) at 485 and 535 nm wavelengths and the percentages of ROS were determined.

Cell Death Analysis with Flow Cytometry

The Fluorescent Isothiocyanate (FITC) Annexin V/Propidium iodide (PI) apoptosis assay kit (BioLegend, Catalog No: 640932) was used to determine apoptosis and necrosis in MCF-7 cells, which were inoculated and incubated in a 6-well plate at 25x10⁵ cells in 2 ml. Then, 25 µM cisplatin and complex-1 compounds were added. After the PDT protocol, the cells were washed with PBS, trypsinized, and the cell suspension was taken into 15 ml falcon tubes 400 µl binding buffer was added to the cells obtained as pellets after the suspended cells were centrifuged at 140 g for 5 minutes. Then, 5 µl of Annexin V and 10 µl of PI were added to the tubes and incubated in the dark for 15 minutes. All groups were tested in triplicates. At the end of the incubation, 400 µl of 1X binding buffer was added to the cells and a reading was made on the BD FacsARIA III (BD Biosciences, Bedford, MA, USA).

Statistical Analysis

The data analysis was expressed as Mean ± SD in the SPSS software package version 26.00 program. Statistical significance between groups was evaluated using One-Way ANOVA and Post-Hoc Tukey Test and p < 0.05 was considered statistically significant.

Single crystals of the complex-1 and 2 were obtained by slow evaporation of acetonitrile solvent. The crystal refinement parameters, selected bond lengths and angles of the complexes are given in Tables 1 and 2. The ORTEP images and atomic numbering scheme of the complexes are given in Fig. 3 with 10% probability level.

The complex-1 has a monoclinic structure and space group P21/c. The phosphine ligand behaved as a tridentate and a chlorine anion (Cl-) bound to the center atom, giving a geometry close to a square plane structure. One chlorine (Cl-) ligand, which was not directly bound to the complex to complement the charge of the center atom, was located on the outer sphere. The distances between the donor atoms and the center atom were measured in the range of 1.983(5) to 2.260(2) Å. In addition, the bond angles measured between the center atom and donor atoms were between 80.02(2) and 95.66(1)^o. The complex-2 has a monoclinic structure and space group P21/c. The phosphine ligand behaved as a tridentate and a chlorine anion (Cl-) bound to the center atom, exhibiting a geometry close to a square plane structure. The distances between the donor atoms directly bonded to the center atom were measured in the range of 1.977(2) to 2.289(9) Å. In addition, the bond angles measured between the center atom and donor atoms were between 79.96(9) and 95.07(8)^o.

Table 1

Crystal data and structure refinement parameters for complex 1 and 2.
Complex 1	Complex 2
CCDC No: 2268993	2268994

Table 2

Selected bond lengths (Å) and angles (^o) of the complex 1 and 2.
Complex 1
Bond Lengths (Å)
Pd(1)-Cl(1)	2.260(2)
Pd(1)-O(1)	2.074(4)
Pd(1)-P(1)	2.186(1)
Pd(1)-N(1)	1.983(5)
Bond Angles (^o)
P(1)-Pd(1)-Cl(1)	89.46(7)
P(1)-Pd(1)-N(1)	95.66(1)
N(1)-Pd(1)-O(1)	80.02(2)
O(1)-Pd(1)-Cl(1)	94.99(1)
Complex 2
Bond Lengths (Å)
Pd(1)-Cl(1)	2.289(9)
Pd(1)-O(1)	2.041(2)
Pd(1)-P(1)	2.197(9)
Pd(1)-N(1)	1.977(2)
Bond Angles (^o)
P(1)-Pd(1)-Cl(1)	91.58(3)
P(1)-Pd(1)-N(1)	95.07(8)
N(1)-Pd( 1)-O(1)	79.96(9)
O(1)-Pd(1)-Cl(1)	93.45(6)

The cytotoxicities, and phototoxicity indices of cisplatin, complex-1 and 2 groups were investigated against MCF-7 cancer cells. Initially, all groups were incubated with MCF-7 cell lines for 72 h in the dark using a half-maximal inhibitory concentration (IC50^dark). In addition, the photocytotoxicities of these complexes were evaluated with an MCF-7 cell line under irradiation with LED followed by incubation for 12 h in the dark. According to these experiments, the cytotoxicity orders in the dark (IC50^dark) were cisplatin > complex-1 > complex-2 against MCF-7. After irradiation, cisplatin and complex 1 showed high photocytotoxicity against the MCF-7 cells (IC50^PDT:12,5 µm) (p < 0.05) (Table 3). The IC50^PDT value of complex 2 (25 µm) against the MCF-7 cells showed the lowest photocytotoxicity (p < 0.05) (Table 3). These results indicate the toxic potential of the compounds by photoactivation on MCF-7 cells. In line with the data obtained here, the optimum agent dose and incubation period were determined (Table 3). Because of the low solubility of the agents used in the present study, it was determined that the solubility increased as the incubation period extended and the cytotoxicity, increased accordingly. In a study conducted by Kumar et al., breast cancer (MCF-7), cervical cancer (Hela), and fibroblast cell line (3T3/NIH) cells were irradiated at 10 J/cm² after 4 hours of incubation with 22.5 µM vanadium-vitamin B6 conjugated SBL and incubated for up to 72 hours. At the end of the experiment, it was found that the cytotoxicity, of the PDT groups in MCF-7 and Hela cell lines were higher than the control group at significant levels, and the cytotoxicity, of the PDT group in 3T3 cells did not show a significant difference when compared to the control group. The differences in some of the data in the present study with other studies might be associated with the cell type, incubation time, PS type and concentration, light exposure time, light strength, and type of light source (Delebe et al. 2015; Chakravarty et al. 2017).

Table 3

IC50 values of MCF-7 cells after 72 hours incubation with cisplatin, complex-1, and complex-2 determined by MTT assay. Dark and photo-toxicity of complexes against MCF-7 breast cancer cells. All data were presented as IC50 ± SD, n = 3. ^ap<0.05 compared with the dark cisplatin group, and ^bp<0.05 compared with the PDT cisplatin group.
Groups	Dark groups IC50 (µm)	PDT Groups IC50 (µm)
Positive Control	26.108 ± 3.125	9.644 ± 17.420
Complex-1	> 50^a	< 50^b
Complex-2	> 50^a	28.45 ± 4.212^b

The ratio of ROS formed by agents on the MCF-7 cell line was tested in the present study with DCFDA (Kumar et al. 2018). In a study conducted by Kumar et al., the light was applied at 10 J/cm² (1 hour) after 4 hours of incubation of Hela cells with vanadium-vitamin B6 conjugated SBL and then incubated until 72 hours. At the end of the trial, it was reported that the ROS level of the PDT group increased at significant levels when compared to the control group (Chakravarty et al. 2017). ROS generation, determined immediately after cell treatments, was significantly enhanced by photoactivated complex-1. The amount of ROS generation was normalized by the non-treated control group. This study showed parallelism with the literature data and it was determined that the ROS levels of the PDT groups were higher than the control group (p < 0.05) (Fig. 4). However, the ROS level of the cisplatin did not differ significantly levels when compared to the complex-1 mediated PDT group (p > 0.05) (Fig. 4). Small but significant increases were noted in cultures treated with the compound without light. ROS generation was affected by UVA It was considered that Pd conjugation to the SBL used in the present study increased the biological activity. Considering the previous studies, it was concluded that the level of ROS might depend on the dose and cell type of the agent. Also, ROS findings showed a significant difference in the dark and PDT groups in the present study when compared to the control group (p < 0.05) (Fig. 4), as in the MTT analysis. Considering this, the cytotoxic effect in the present study was associated with ROS (Sai et al. 2021; Sharman et al. 2000). These results indicated that singlet oxygens generated from compounds reacted preferentially with cellular components, resulting in elevated ROS levels and cell damage.

The apoptotic and necrotic types of cell death were determined with the Annexin V kit in the present study. In a study conducted by Eskiler et al., MCF-7 and MDA-MB-231 cells were irradiated with a diode laser at 0, 6, 9, and 12 J/cm² after 4 hours of incubation with 1 mM 5-ALA and after 24 hours of incubation, PDT group (12 J/cm²), and it was reported that the rate of early apoptosis increased at significant levels when compared to the other PDT groups and the control group (Eskiler et al. 2020). The present study showed different results from the study of Eskiler et al. Late apoptosis was detected in PDT groups (p < 0.05) (Fig. 5) but early apoptosis was not detected (p > 0.05) (Fig. 5). Early apoptosis is detected with the Annexin V Kit before the membrane integrity of the cells is impaired, and late apoptosis is detected at the stage where the cell membrane loses its integrity (Martin et al. 1995). Phosphatidylserine is displaced from the plasma membrane on the cytoplasmic face to the outer membrane in the early stage of apoptosis. Effector molecules such as Bcl-2 and enzymes such as flippase, floppase, and scramblase are involved in the phosphatidylserine translocase (Martin et al. 1995; Blankenberg and Norfray 2011). It was suggested in some studies that when the light dose is high in PDT, necessary molecules and enzymes that play roles in cell death become ineffective (Xue et al. 2001). It was also reported that phosphatidylserine is oxidized before migration outside the cell membrane by ROS production, but that phosphatidylserine is blocked by the anti-apoptotic Bcl-2 ((Xue et al. 2001). It was concluded in the present study that the absence of early apoptosis might be associated with the light dose and the inactivation of molecules and enzymes involved in early apoptosis; however, despite this, ROS production and cell death continue. In a previous study, MCF7 cells were irradiated at 4 J/cm² after 4 hours of incubation with 15 µM Tamoxifen and 2 µM Hypericin, which is a PS, and incubated for 24 hours. Although early and late apoptosis was not detected in the PDT group, necrosis was found (Theodossiou et al. 2019). Similar to this study, necrosis was found rather than late apoptosis in the present study (p < 0.05) (Fig. 5) in the PDT groups (p < 0.05) (Fig. 5). Cell death by light activation is associated with different factors, including the concentration and intracellular localization of PS, its physicochemical properties, oxygen concentration, wavelength and intensity of light, and cell type (Ibbotson 2010; Muniyandi et al. 2020). It is reported in the literature that low-dose agents and light cause a higher rate of apoptotic death in PDT, and higher doses cause more necrotic deaths (Noodt et al. 1996; Mroz et al. 2011). We think that the high level of necrosis was associated with the dose of the agent and the dose of light in the present study. On the other hand, it was reported in some studies that if PS is localized to the plasma membrane, ROS and singlet oxygen formed as a result of the application of light disrupts the integrity of the membrane by inducing peroxidation of cholesterol and phospholipids in the membrane structure, and result in necrosis (Mroz et al. 2011; Delebe et al. 2015). For this reason, it was concluded that necrosis might be because of the photochemical reactions that occur with the localization of the agents we use on the membrane in the present study.

The present study showed that complex-1-mediated PDT was similar to cisplatin-mediated PDT in terms of causing ROS production, and cell death. We conclude that complex-1-mediated PDT instigates mitochondrial apoptosis, potentially exerting in vitro anti-tumor effects. Moreover, complex-1 seems to trigger cancer cell death through ROS levels, and late apoptosis, implying a multi-targeted mechanism. We hypothesized that complex-2-mediated PDT was linked with poor or no anticancer action on the MCF-7 cell line based on our early findings. We concluded that the newly developed and synthesized PS agents can lead to new investigations to assess their anticancer properties and the creation of novel treatment methods based on the data we acquired.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to infuence the work reported in this paper.

Acknowledgments

The experiments of this study were conducted at the Advanced Technology Education Research and Application Center. This work was supported by the Research Fund of Mersin University in Turkey (grant number: 2021-1-TP3-4351).

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SupplementaryFile.docx

Investigation of the Anti-Cancer of Photodynamic Therapy Effects by Using the Novel Schiff-Base Ligand Complex on Human Breast Cancer Cell Line

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