Human Oral Cancer Cells Research Articles

Sorafenib potentiates ABT-737-induced apoptosis in human oral cancer cells

ObjectiveThe mimetic BH3 ABT-737, a potent inhibitor of anti-apoptotic Bcl-2 family proteins, has potential as anti-cancer drug in many cancers. Recently, patients treated with ABT-737 have developed drug tolerance during cancer therapy. Therefore, we examined whether ABT-737 is effective in killing MC-3 and HSC-3 human oral cancer cells either alone or in combination with the oncogenic kinase inhibitor, sorafenib. DesignThe potentiating activities of sorafenib in ABT-737-induced apoptosis were determined using trypan blue exclusion assay, DAPI staining, cell viability assay and Western blot analysis. ResultsCombined use of ABT-737 and sorafenib synergistically suppressed cell viability and induced apoptosis compared with either compound individually. The combination of ABT-737 and sorafenib altered only Bax and Bak proteins and their activations, resulting in mitochondrial translocation of Bax from the cytosol. Additionally, combination treatment-mediated apoptosis may be correlated with ERK and STAT3 pathways. ConclusionsThese results suggest that sorafenib may effectively overcome ABT-737 resistance to apoptotic cell death, which can be a new potential chemotherapeutic strategy against human oral cancer.

BH3 mimetic Obatoclax (GX15-070) mediates mitochondrial stress predominantly via MCL-1 inhibition and induces autophagy-dependent necroptosis in human oral cancer cells

We have previously reported overexpression of antiapoptotic MCL-1 protein in human oral cancers and its association with therapy resistance and poor prognosis, implying it to be a potential therapeutic target. Hence, we investigated the efficacy and mechanism of action of Obatoclax, a BH3 mimetic pan BCL-2 inhibitor in human oral cancer cell lines. All cell lines exhibited high sensitivity to Obatoclax with complete clonogenic inhibition at 200–400 nM concentration which correlated with their MCL-1 expression. Mechanistic insights revealed that Obatoclax induced a caspase-independent cell death primarily by induction of a defective autophagy. Suppression of autophagy by ATG5 downregulation significantly blocked Obatoclax-induced cell death. Further, Obatoclax induced interaction of p62 with key components of the necrosome RIP1K and RIP3K. Necrostatin-1 mediated inhibition of RIP1K significantly protected the cells from Obatoclax induced cell death. Moreover, Obatoclax caused extensive mitochondrial stress leading to their dysfunction. Interestingly, MCL-1 downregulation alone caused mitochondrial stress, highlighting its importance for mitochondrial homeostasis. We also demonstrated in vivo efficacy of Obatoclax against oral cancer xenografts and its synergism with ionizing radiation in vitro. Our studies thus suggest that Obatoclax induces autophagy-dependent necroptosis in oral cancer cells and holds a great promise in the improved management of oral cancer patients.

Synthesis of Colloidal Quantum Dots Coated with Mercaptosuccinic Acid for Early Detection and Therapeutics of Oral Cancers

Quantum dots (QDs) are gaining widespread recognition for its luminescence behavior and unique photo physical properties as a bio-marker and inorganic fluorophore. In spite of such rampant advantages, its application is clinically hampered depending on the surface coating decreasing its luminescence efficiency. The present study reports preparation of CdTe QDs capped with biologically active thiol based material, mercaptosuccinic acid (MSA) for diagnosis of oral cancer (KB) cells by acting as a fluorophore marking targeted tumor cells and at the same time exhibiting certain cytotoxic effects. Synthesized MSA coated CdTe QDs is spherical in shape with an average particle size of 3–5[Formula: see text]nm. In vitro, the rapid uptake of MSA CdTe QDs in oral cancer cell lines were assessed through fluorescence microscopy. Further, this study evaluates the therapeutic efficiency of MSA CdTe QDs in human oral cancer cell lines using MTT analysis. MSA CdTe QDs exhibit significant cytotoxicity in oral cancer cells in a dose dependent manner with low IC50 when compared with other raw CdTe QDs. MSA CdTe QDs were also treated with human lymphocytes (normal cells) to assess and compare the toxicity profile of QDs in normal and oral tumors. The results of our present study strengthen our hypothesis of using MSA CdTe QDs as detector for tracking and fluorescence imaging of oral cancer cells and exhibiting sufficient cytotoxicity in them.

Antimalarial and cytotoxic quassinoids from the roots of Brucea javanica

Two new quassinoids, brujavanol A (1) and brujavanol B (2), along with five known quassinoids (3–7), were isolated from the roots of Brucea javanica. Their structures were elucidated by spectroscopic methods. The antimalarial and cytotoxic activities of the isolated compounds were also assessed. Compounds 1 and 2 exhibited significant in vitro cytotoxicity against human oral cavity cancer (KB) cells with IC50 values of 1.30 and 2.36 μg/ml, respectively, whereas compound 3 showed excellent antiplasmodial activity against the Plasmodium falciparum strains, K1 (IC50 = 0.58 μg/ml).

Anti-proliferative and apoptotic effects of quinine in human Hep-2 laryngeal cancer and KB oral cancer cell

<p>The present study evaluated the anti-proliferative and apoptotic effect of quinine on oral cancer cells Hep-2 and KB. Cell inhibition, apoptosis and anti-inflammatory effects were explored by nuclear DNA cleavage, condensation, change in membrane potential of mitochondria. Meanwhile, inflammatory and apoptosis-related mRNA and proteins expressions such as iNOS COX-2, IL-6, Bcl-2, mutant p53, Bax, caspase-3 and NF-κB were determined by RT-PCR and Western blotting assays. Results showed that, quinine treatment significantly inhibited the cell viability and colony formation, inhibited cell proliferation lead to increased generation of reactive oxygen species induction of MMP depolarization, morphological changes and DNA damage in dose- and time-dependent manner. Moreover, quinine significantly decreased the iNOS, COX-2, IL-6, Bcl-2 and mutant p53 simultaneously up-regulated Bax, caspase-3 expressions through the inhibition of NF-κB suggest that quinine may serve as a potential candidate in the prevention of cell proliferation and enhances apoptosis via inhibiting up-stream signalling.</p><p><strong>Video Clip</strong></p><p><a href="https://youtube.com/v/83HX2fFTXkg">Programmed cell death assay by dual staining:</a> 17 min 25 sec</p><p> </p>

Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways.

Multidrug resistance (MDR) is considered to be the major contributor to failure of chemotherapy in oral squamous cell carcinoma (SCC). This study was aimed to explore the effects and mechanisms of glaucarubinone (GLU), one of the major quassinoids from Simarouba glauca DC, in potentiating cytotoxicity of paclitaxel (PTX), an anticancer drug in KB cells. Our data showed that the administration of GLU pre-treatment significantly enhanced PTX anti-proliferative effect in ABCB1 over-expressing KB cells. The Rh 123 drug efflux studies revealed that there was a significant transport function inhibition by GLU-PTX treatment. Interestingly, it was also found that this enhanced anticancer efficacy of GLU was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Further, the combined treatment of GLU-PTX had significant decrease in the expression levels of P-gp, MRPs, and BCRP in resistant KB cells at both mRNA and protein levels. Furthermore, the combination treatments showed significant reactive oxygen species (ROS) production, chromatin condensation and reduced mitochondrial membrane potential in resistant KB cells. The results from DNA fragmentation analysis also demonstrated the GLU induced apoptosis in KB cells and its synergy with PTX. Importantly, GLU and/or PTX triggered apoptosis through the activation of pro-apoptotic proteins such as p53, Bax, and caspase-9. Our findings demonstrated for the first time that GLU causes cell death in human oral cancer cells via the ROS-dependent suppression of MDR transporters and p53-mediated activation of the intrinsic mitochondrial pathway of apoptosis. Additionally, the present study also focussed on investigation of the protective effect of GLU and combination drugs in human normal blood lymphocytes. Normal blood lymphocytes assay indicated that GLU is able to induce selective toxicity in cancer cells and in silico molecular docking studies support the choice of GLU as ABC inhibitor to enhance PTX efficacy. Thus, GLU has the potential to enhance the activity of PTX and hence can be a good alternate treatment strategy for the reversal of PTX resistance.

Composition of the Leaf Essential Oil of Phoebe formosana from Taiwan and its in vitro Cytotoxic, Antibacterial, and Antifungal Activities

The essential oil from the leaves of Phoebe formosana from Taiwan was isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC-FID and GC-MS. Seventy-one compounds were identified, representing 100% of the oil. The main components identified were a-humulene (16.8%), τ-cadinol (8.9%), α-pinene (8.4%), α-cadinol (8.1%), β-caryophyllene (8.0%), β-phellandrene (6.0%), and β-eudesmol (5.8%). The oil exhibited cytotoxic activity against human lung, liver and oral cancer cells. The active compounds were β-caryophyllene, α-humulene, τ-cadinol, β-eudesmol, and α-cadinol. The antibacterial activity of the oil was tested by the disc diffusion and micro-broth dilution methods against eight bacterial species. The oil exhibited moderate growth suppression against Gram-positive bacteria with inhibition zones of 28 to 36 mm, and MIC values of 250 to 375 μg/mL. The active antibacterial compounds were determined to be τ-cadinol, β-eudesmol, and α-cadinol. The leaf oil displayed excellent antifungal activity with the active compounds determined as α-cadinol, β-eudesmol, τ-cadinol, α-humulene, and β-caryophyllene.

Anti-Cancer Effects of Imperata cylindrica Leaf Extract on Human Oral Squamous Carcinoma Cell Line SCC-9 in Vitro.

Imperata cylindrica, a tall tufted grass which has multiple pharmacological applications is one of the key ingredients in various traditional medicinal formula used in India. Previous reports have shown that I. cylindrica plant extract inhibited cell proliferation and induced apoptosis in various cancer cell lines. To our knowledge, no studies have been published on the effect of I. cylindrica leaf extract on human oral cancers. The present study was undertaken in order to evaluate the anticancer properties of the leaf extract of I. cylindrica using an oral squamous cell carcinoma cell line SCC-9 as an in vitro model system. A methanol extract from dried leaves of I. cylindrica (ICL) was prepared by standard procedures. Effects of the ICL extract on the morphology of SCC-9 cells was visualized by microscopy. Cytotoxicity was determined by MTT assay. Effects of the ICL extract on colony forming ability of SCC-9 cells was evaluated using clonogenic assay. Cell cycle analysis was performed by flow cytometry and induction of apoptosis was determined by DNA fragmentation assay. The ICL extract treatment caused cytotoxicity and induced cell death in vitro in SCC-9 cells in a dose-dependent manner. This treatment also significantly reduced the clonogenic potential and inhibited cell proliferation by arresting the cell cycle in the G2/M phase. Furthermore, DNA fragmentation assays showed that the observed cell death was caused by apoptosis. This is the first report showing the anticancer activity of the methanol extracts from the leaves of I. cylindrica in human oral cancer cell line. Our data indicates that ICL extract could be considered as one of the lead compounds for the formulation of anticancer therapeutic agents to treat/manage human oral cancers. The natural abundance of I. cylindrica and its wide geographic distribution could render it one of the primary resource materials for preparation of anticancer therapeutic agents.

4-Hydroxybutenolide impairs cell migration, and invasion of human oral cancer SCC-4 cells via the inhibition of NF-κB and MAPK signaling pathways.

4-Hydroxybutenolide (K87), a synthetic compound from furfuryl alcohol via photooxidation, was used to investigate whether it can inhibit mobility, migration and invasion of SCC-4 human oral cancer cells invitro. Cell viability was measured by flow cytometric assay, the enzymatic activities of MMP-2/9 were assayed by gelatin zymography analysis, the protein levels were assayed by western blotting, confocal laser microscopy and EMSA assay, and the gene expression of MMP-2/-7, FAK and ROCK1 mRNA were assayed by PCR. K87 decreased the percentage of viable cells in dose-dependent manner. K87 suppressed cell mobility, migration and invasion of SCC-4 cells dose-dependently. K87 inhibited the enzymatic activities of MMP-2/9 of SCC-4 cells. Western blot analysis revealed that K87 decreased the protein levels in NF-κBp65, COX-2, ROCK1 and Rho A, MMP-1, -2,- 7, -9, VEGF, GRB2, SOS1, PI3K, PKC, PERK, p-PERK, FAK, MEKK3, MKK7, ERK1/2, JNK1/2, p-p38, p38, p-c-Jun, AKT, TIMP2, but increased the protein levels of iNOS, Ras, IRE-1α, p-c-JNK, p-AKT(308), p-AKT(473) and TIMP1. Results from PCR indicated that K87 inhibited the gene expression of MMP-2/-7, FAK and ROCK1 mRNA. Furthermore, confocal laser microscopy was used to confirm that K87 inhibited the translocation of RHOA and ROCK1 in SCC-4 cells. EMSA assay also show that K87 suppressed the nuclear activation of NF-κB and these effects are time-dependent. Western blotting assay indicated that expression of NF-κBp105, NF-κBp50 and NF-κBp65 proteins were decreased and these effects are time-dependent. Based on these observations, we suggest that K87 may be used as a potential agent for anticancer metastasis of human oral cancer in the future.

Tumor Growth and Cell Proliferation Rate in Human Oral Cancer

Oral squamous cell cancer (SCC) has a high rate of morbidity and an overall 5-year survival rate for patients of 50%, statistics that have not changed in the last half century. A better understanding of the biological nature of this aggressive disease is mandatory. The two most studied human oral cancer cell lines-SCC-15 and SCC-25-share some biological characteristics but differ in others and may serve as a platform for further oral SCC analysis. We compared their basic carcinogenic characteristics, cellular proliferation rate and tumor growth, and discussed results according to available data from the literature and our own previous studies. We examined doubling time both invitro and invivo of the SCC-15 and SCC-25cell lines. After seeding the exact same number of cells in a six-well dish we counted them daily. To confirm doubling time differences in cells, we progressed to an invivo model in nude mice using male 9- to 10-week-old BALB/c-nu/nu mice. In both models (invitro and invivo) SCC-15 multiplied faster than SCC-25cell line. Invivo the difference was more than double and invitro this change was 24%. Both SCC-15 and SCC-25cell lines are suitable for further exploration of the oral carcinogenesis process. Based on our currently presented results and on the available literature, it seems that SCC-15 has an increased potential for local tumor growth and cell proliferation, whereas SCC-25 has a higher potential for invasion and metastasis.

Metformin induces apoptosis by microRNA-26a-mediated downregulation of myeloid cell leukaemia-1 in human oral cancer cells.

In recent years, population-based studies and retrospective analyses of clinical studies have shown that metformin treatment is associated with reduced cancer incidence and a decrease in cancer‑associated mortality. However, its mechanism of action remains to be fully understood. The present study demonstrates the effects of metformin on KB human oral cancer cells and explores the role of myeloid cell leukaemia‑1 (Mcl‑1) in metformin‑induced mitochondria‑dependent cellular apoptosis. It was demonstrated that metformin exposure caused significant suppression of KB cell proliferation and induced cell death. Furthermore, metformin induced apoptosis through the downregulation of Mcl‑1 in KB human oral cancer cells, and the overexpression of Mcl‑1 in metformin‑treated KB cells significantly increased cell viability. Consistently, Bax and Bim were upregulated in metformin‑treated cells. The results also reveal that microRNA (miR)‑26a expression was markedly increased by metformin. Subsequent to enforced miR‑26a expression in KB cells using miR‑26a mimics, cell viability and the level of Mcl‑1 decreased. These results suggest that the anti‑proliferative effects of metformin in KB cells may result partly from induction of apoptosis by miR-26a-induced downregulation of Mcl-1.

ER‐Dependent Ca++‐Mediated Production of Cytosolic ROS as an Effector for Induction of Mitochondrial Apoptotic Signal and ATM in Gallic Acid‐treated Human Oral Cancer Cell

Release of calcium (Ca++) from the endoplasmic reticulum (ER) has been proposed to be involved in induction of apoptosis by oxidative stress. Using ER Ca++ release inhibitor dantrolene and mitochondrial Ca++ uptake inhibitor Ru‐360, we demonstrated that Ca++ release from the ER was associated with loss of mitochondrial membrane potential, increase in reactive oxygen species (ROS), and apoptosis of human oral cancer (OC) cells induced by gallic acid (GA). Chemical chaperone 4‐phenylbutyrate inhibits tunicamycin‐induced induction of 78 kDa glucose‐regulated protein, C/EBP homologous protein and pro‐caspase‐12 cleavage, cytosolic Ca++ increase, and apoptosis, but did not attenuate the increase in cytosolic Ca++ level and apoptosis induced by GA. Ataxia telangiectasia mutated (ATM)‐mediated c‐Jun N‐terminal kinase (JNK) phosphorylation and apoptosis in response to GA was blocked by dantrolene. The specificity of ROS‐mediated ATM activation was confirmed by the treatment of N‐acetylcysteine, an ROS scavenger. Blockade of ATM activation by a specific inhibitor KU55933, short hairpin RNA, or kinase‐dead ATM overexpression suppressed JNK phosphorylation but did not completely inhibit cytosolic ROS production, mitochondrial cytochrome c release, pro‐caspase‐3 cleavage, and apoptosis induced by GA. When taken together, these results indicate that GA induces OC cell apoptosis by inducing the activation of mitochondrial apoptotic signal and ATM, likely through ER Ca++‐mediated ROS production.Support or Funding Information

Intracellular interactions of electrostatically mediated layer-by-layer assembled polyelectrolytes based sorafenib nanoparticles in oral cancer cells

In this paper, we report the preparation of LbL-nanoSraf (100–300nm) comprising of layer-by-layer (LbL) assembled polyelectrolytes dextran-sulfate/poly-l-arginine, with a multikinase inhibitor sorafenib (Sraf) encapsulated calcium carbonate (CaCO3) nanoparticles for oral cancer therapy in vitro. The zeta potential of LbL-nanoSraf exhibited a negative charge of the polyanionic dextran sulfate, which alternated with a positive charge of polycationic poly-l-arginine indicating a successful LbL assembly of the two polyelectrolyte bilayers on the CaCO3 nanoparticles. The LbL-nanoSraf exhibited an encapsulation efficiency of 61±4%. The LbL-nanoSraf was characterized using field-emission gun scanning electron microscopy, X-ray powder diffraction, atomic force microscopy and confocal laser scanning microscopy. Confocal laser scanning microscopy, flow cytometry and transmission electron microscopic investigations showed the internalization of LbL-nanoSraf in human oral cancer (KB) cells. The LbL-nanoSraf exhibited more potent antiproliferative, apoptotic and antimigratory activities in KB cells than the free drug Sraf. The findings could promote the application of nano-sized LbL assembled polyelectrolytes for the delivery of Raf-kinase inhibitors and provide mechanistic insights for oral cancer therapy.

Synergetic Effects of PARP Inhibitor AZD2281 and Cisplatin in Oral Squamous Cell Carcinoma in Vitro and in Vivo.

Cisplatin is a commonly used chemotherapeutic drug for treatment of oral carcinoma, and combinatorial effects are expected to exert greater therapeutic efficacy compared with monotherapy. Poly(ADP-ribosyl)ation is reported to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, and genomic stability. Based on these properties, poly(ADP-ribose) polymerase (PARP) inhibitors are used for treatment of cancers, such as BRCA1/2 mutated breast and ovarian cancers, or certain solid cancers in combination with anti-cancer drugs. However, the effects on oral cancer have not been fully evaluated. In this study, we examined the effects of PARP inhibitor on the survival of human oral cancer cells in vitro and xenografted tumors derived from human oral cancer cells in vivo. In vitro effects were assessed by microculture tetrazolium and survival assays. The PARP inhibitor AZD2281 (olaparib) showed synergetic effects with cisplatin in a dose-dependent manner. Combinatorial treatment with cisplatin and AZD2281 significantly inhibited xenografted tumor growth compared with single treatment of cisplatin or AZD2281. Histopathological analysis revealed that cisplatin and AZD2281 increased TUNEL-positive cells and decreased Ki67- and CD31-positive cells. These results suggest that PARP inhibitors have the potential to improve therapeutic strategies for oral cancer.

Retracted: Knockdown of tumor protein D52-like 2 induces cell growth inhibition and apoptosis in oral squamous cell carcinoma.

The above article, published online on 13 October 2014 in Wiley Online Library (http://onlinelibrary.wiley.com/doi/10.1002/cbin.10388/abstract), has been retracted by agreement between the authors, the journal Editor, Sergio Schenkman, and John Wiley & Sons Ltd. The retraction has been agreed because the authors discovered after publication that one of the cell lines described in the article had been unintentionally misidentified. The experiments described in the article as being conducted on Human Oral Squamous Cell Carcinoma cell line KB were in fact conducted on a Human Oral Epidermal-like Cancer cell line. The authors and publisher apologise for any inconvenience. References He Y, Chen F, Cai Y and Chen S (2015) Knockdown of tumor protein D52-like 2 induces cell growth inhibition and apoptosis in oral squamous cell carcinoma. Cell Biology International 39: 264-271. doi: 10.1002/cbin.10388.

Tetrandrine induces programmed cell death in human oral cancer CAL 27 cells through the reactive oxygen species production and caspase-dependent pathways and associated with beclin-1-induced cell autophagy.

Tetrandrine, a bisbenzylisoquinoline alkaloid, is extracted from the root of the Chinese herb Radix Stephania tetrandra S Moore. This compound has antitumor activity in different cancer cell types. In this study, the effects of tetrandrine on human oral cancer CAL 27 cells were examined. Results indicated that tetrandrine induced cytotoxic activity in CAL 27 cells. Effects were due to cell death by the induction of apoptosis and accompany with autophagy and these effects were concentration- and time-dependent manners. Tetrandrine induced apoptosis was accompanied by alterations in cell morphology, chromatin fragmentation, and caspase activation in CAL 27 cells. Tetrandrine treatment also induced intracellular accumulation of reactive oxygen species (ROS). The generation of ROS may play an important role in tetrandrine-induced apoptosis. Tetrandrine triggered LC3B expression and induced autophagy in CAL 27 cells. Tetrandrine induced apoptosis and autophagy were significantly attenuated by N-acetylcysteine pretreatment that supports the involvement of ROS production. Tetrandrine induced cell death may act through caspase-dependent apoptosis with Beclin-1-induced autophagy in human oral cancer cells. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 329-343, 2017.

Phenethyl isothiocyanate enhances TRAIL-induced apoptosis in oral cancer cells and xenografts.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been regarded as a promising candidate for cancer therapy. However, most of oral cancer cell lines are resistant to the TRAIL-induced cytotoxicity. The aim of this study was to investigate the ability of phenethyl isothiocyanate (PEITC) to sensitize TRAIL-induced apoptosis in TRAIL-resistant oral cancer cells and xenografts. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, Western blotting, and a mouse xenograft model were used to study the effects of PEITC and TRAIL on two TRAIL-resistant human oral cancer cells, SAS and Ca9-22. PEITC upregulated death receptor 4 (DR4) and DR5 protein expression and increased reactive oxygen species (ROS) production in both SAS and Ca9-22 cells. Antioxidant N-acetyl-L-cysteine (NAC) and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 inhibited PEITC-induced DR4 and DR5 expression. Inhibitor experiments showed that PEITC induced apoptosis through ROS-mediated JNK activation and upregulation of DR4 and DR5. Furthermore, treatment with PEITC significantly increased TRAIL-induced apoptosis in both cells. Combined treatment with PEITC and TRAIL had greater effect on the inhibition of tumor growth than either agent alone. We showed for the first time that PEITC overcomes TRAIL resistance in oral cancer cells and enhance the therapeutic potential of TRAIL in vivo. PEITC, either alone or in combination with TRAIL, can be used as a new therapeutic approach for the treatment of oral cancers.

Syntheses of Platinum-Sulindac Complexes and Their Nanoparticles as Targeted Anticancer Drugs.

Platinum(II)-sulindac complexes [{η2 -C5 H4 SN(O)}Pt(DMSO){O(C=O)Sulindac}], [{η2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac}], [{η2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac-succinimide}], and [{η2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac-thymidine}] were synthesized that exhibited IC50 values of 2.9-4.8 μm against human oral cancer cells OECM1. The poly(lactic-co-glycolic acid) (PLGA) encapsulated [{η2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac}] also showed cytotoxic activity although less potent than the pristine species.

Myeloid cell leukemia-1 is a molecular indicator for malignant transformation of oral lichen planus

Oral lichen planus (OLP), characterized by a chronic mucocutaneous inflammatory condition, is a common disease of the oral cavity. Retrospective and prospective epidemiological data suggest that OLP is considered to have malignant potential. However, it is unclear as to which types of molecules may cause malignant transformation of OLP. In the present study, the presence of myeloid cell leukemia-1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) was studied by western blot analysis in 11 OLP and three normal oral mucosa (NOM) samples and in two human oral cancer cell lines. The functional role of Mcl-1 in oral cancer cells was analyzed using a trypan blue exclusion assay and soft agar assay. Mcl-1 was strongly expressed in the OLP and the two oral cancer cell lines compared with NOM, whereas Bcl-2 was not. Sorafenib and mithramycin A decreased cell viability in MC-3 and HSC-3 oral cancer cells and at same concentration they reduced the expression level of Mcl-1 in the two cell lines. The two chemicals affected Mcl-1 protein and significantly inhibited neoplastic cell transformation in the two cell lines. We suggest that the malignant potential of OLP may be associated with the expression of Mcl-1, and that downregulation of Mcl-1 may prevent malignant transformation of OLP to oral cancer.

6‐Gingerol Mediates its Anti Tumor Activities in Human Oral and Cervical Cancer Cell Lines through Apoptosis and Cell Cycle Arrest

6-Gingerol, a potent nutraceutical, has been shown to have antitumor activity in different tumors, although its mechanism of action is not well understood. In this study, we evaluated antitumor activities of 6-gingerol on human oral (SCC4, KB) and cervical cancer (HeLa) cell lines with or without wortmannin, rapamycin, and cisplatin. Tumor cell proliferation was observed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium, inner salt assay, cell cycle analysis by propidium iodide labeling and flow cytometry, apoptosis by Annexin-V binding assay, and caspase activity by chemiluminescence assay. 6-Gingerol showed dose-dependent cytotoxicity in all three cell lines. Combinations of 6-gingerol with wortmannin and cisplatin showed additive effects, while with rapamycin, it showed 50% cytotoxicity that was equivalent to IC50 of 6-gingerol alone. Treatment with 6-gingerol resulted in G2-phase arrest in KB and HeLa cells and S-phase arrest in SCC4 cells. 6-Gingerol, wortmannin, and rapamycin treatment showed almost two-fold higher expression of caspase 3 in all cell lines. The results imply that 6-gingerol either alone or in combination with PI-3 K inhibitor and cisplatin may provide better therapeutic effects in oral and cervical carcinoma. Thus, 6-gingerol appears to be a safe and potent chemotherapeutic/chemopreventive compound acting through cell cycle arrest and induction of apoptosis in human oral and cervical tumor cells.