Figure 1 - uploaded by Nilesh Kumar Sharma Ph.D. FMASc.
Content may be subject to copyright.
Source publication
Introduction: Cisplatin has been considered as the crucial regimen of widely prescribed chemotherapy treatment for cancer. The advancing treatment of cancers has reached the border line, where tumors show resistance to cisplatin and may thwart its use. Other than issues of drug resistance, cisplatin has been reported to evince side effects such as...
Contexts in source publication
Context 1
... sometimes, 1,3-intra-strand or inter-strand adducts are formed but 85-90% of lesions caused are ApG and GpG adducts formed by 1,2-intra-strand crosslinks [11,16]. Other than DNA, cisplatin has been reported to interact with biomolecules such as bind to RNA, proteins, membrane phos- pholipids and cytoskeleton forming microfilaments (Figure 1) [5][6][7][8][9][10][11][12][13][14]. ...
Context 2
... precisely, p53 has been indi- cated to work independently for the activation of several genes such as DNA damage inducible gadd45a gene and pro-apoptotic Bax gene [11,16]. There is a report on the apop- totic pathway induction by cisplatin, which is influenced by the increased ratio of Bax and Bcl2, where Bcl2 is an antia- poptotic protein (Figure 1) [9][10][11][12][13][14][15][16]. Other than p53, p73 can also induce apoptosis with help of c-Abl tyrosine kinase. ...
Similar publications
Gentamicin (GM) is used for neonates as the initial treatment for neonatal bacterial infection. An association between high trough GM levels and the elevation of the serum creatinine (sCr) level and hearing loss has been reported, although there have been no reports investigating the serial changes in the sCr level in preterm neonates treated with...
Ototoxicity is the pharmacological adverse reaction affecting the inner ear or auditory nerve, characterized by cochlear or vestibular dysfunction. The panorama of drug-induced hearing loss has widened over last few decades. Although ototoxic medications play an imperative role in modern medicine, they have the capacity to cause harm and lead to si...
Evaluating risks associated with multiple occupational exposures is no easy task, especially when chemical and physical nuisances are combined. In most countries, public institutions have created databases, which gather extensive information on occupational exposures or work-related diseases. Unfortunately, these tools rarely integrate medical and...
Citations
... Although it is a well-established, safe, and cost-effective treatment for patients, cisplatin has clinical drawbacks associated with its relatively high toxicity and the rapid development of chemoresistance that is seen in many tumours [10]. Wide differences in its effectiveness also stem from the variety of clinical approaches used for drug delivery [11][12][13]. Thus, the optimisation of cisplatin efficiency [14,15] and the minimisation of cisplatin chemoresistance [16] are the most important approaches that could improve patient treatment and prognosis. ...
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with complex carcinogenesis. Although there has been significant progress in the treatment of HCC over the past decades, drug resistance to chemotherapy remains a major obstacle in its successful management. In this study, we were able to reduce chemoresistance in cisplatin-resistant HepG2 cells by either silencing the expression of transglutaminase type 2 (TG2) using siRNA or by the pre-treatment of cells with the TG2 enzyme inhibitor cystamine. Further analysis revealed that, whereas the full-length TG2 isoform (TG2-L) was almost completely cytoplasmic in its distribution, the majority of the short TG2 isoform (TG2-S) was membrane-associated in both parental and chemoresistant HepG2 cells. Following the induction of cisplatin toxicity in non-chemoresistant parental cells, TG2-S, together with cisplatin, quickly relocated to the cytosolic fraction. Conversely, no cytosolic relocalisation of TG2-S or nuclear accumulation cisplatin was observed, following the identical treatment of chemoresistant cells, where TG2-S remained predominantly membrane-associated. This suggests that the deficient subcellular relocalisation of TG2-S from membranous structures into the cytoplasm may limit the apoptic response to cisplatin toxicity in chemoresistant cells. Structural analysis of TG2 revealed the presence of binding motifs for interaction of TG2-S with the membrane scaffold protein LC3/LC3 homologue that could contribute to a novel mechanism of chemotherapeutic resistance in HepG2 cells
... Furthermore, a high incidence of chemotherapy resistance is frequently observed in HCC, especially after long-term use of chemotherapy [8]. Cisplatin (cis-diammine-dichloroplatinum) is an essential component of standard chemotherapy for gastrointestinal, respiratory, and genitourinary cancers [9]. Although multidrug regimens have higher response rates for HCC than monotherapy with cisplatin, the efficacy remains unsatisfactory. ...
Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has potential anticancer activities against various types of cancers. However, the effects of the combination of adenine and cisplatin on hepatocellular carcinoma (HCC) cells remain sketchy. Here, our objective was to elucidate the anticancer activity of adenine in combination with cisplatin in HCC cells and its mechanistic pathways. Cell viability and cell cycle progression were assessed by the SRB assay and flow cytometry, respectively. Apoptosis was demonstrated by PI/annexin V staining and flow cytometric analysis. Protein expression, signaling cascade, and mRNA expression were analyzed by Western blotting and quantitative RT-PCR, respectively. Our results showed that adenine jointly potentiated the inhibitory effects of cisplatin on the cell viability of SK-Hep1 and Huh7 cells. Further investigation showed that adenine combined with cisplatin induced higher S phase arrest and apoptosis in HCC cells. Mechanically, adenine induced AMPK activation, reduced mTOR phosphorylation, and increased p53 and p21 levels. The combination of adenine and cisplatin synergistically reduced Bcl-2 and increased PUMA, cleaved caspase-3, and PARP in HCC cells. Adenine also upregulated the mRNA expression of p53, p21, PUMA, and PARP, while knockdown of AMPK reduced the increased expression of these genes. Furthermore, adenine also induced the activation of p38 MAPK through AMPK signaling, and the inhibition of p38 MAPK reduced the apoptosis of HCC cells with exposure to adenine combined with cisplatin. Collectively, these findings reveal that the combination of adenine and cisplatin synergistically enhances apoptosis of HCC cells, which may be attributed to the AMPK-mediated p53/p21 and p38 MAPK cascades. It suggests that adenine may be a potential adjuvant for the treatment of HCC in combination with cisplatin.
... After 6 h of treatment with DMC, HeLa cells showed no change in the number of cells in the G 0 /G 1 and G 2 /M phases. However, after 12-48 h of DMC treatment, the number of HeLa cells in the G 0 /G 1 phase was increased, which indicates the inhibition of CDK/cyclin complexes by p16 and p21 following DNA damage and p53 activation, similar to that observed after 5-fluorouracil and cisplatin treatment for 48 h [36][37][38][39]. ...
2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC), a natural product derived from Syzygium nervosum A. Cunn. ex DC., was investigated for its inhibitory activities against various cancer cell lines. In this work, we investigated the effects of DMC and available anticervical cancer drugs (5-fluorouracil, cisplatin, and doxorubicin) on three human cervical cancer cell lines (C-33A, HeLa, and SiHa). DMC displayed antiproliferative cervical cancer activity in C-33A, HeLa, and SiHa cells, with IC50 values of 15.76 ± 1.49, 10.05 ± 0.22, and 18.31 ± 3.10 µM, respectively. DMC presented higher antiproliferative cancer activity in HeLa cells; therefore, we further investigated DMC-induced apoptosis in this cell line, including DNA damage, cell cycle arrest, and apoptosis assays. As a potential anticancer agent, DMC treatment increased DNA damage in cancer cells, observed through fluorescence inverted microscopy and a comet assay. The cell cycle assay showed an increased number of cells in the G0/G1 phase following DMC treatment. Furthermore, DMC treatment-induced apoptosis cell death was approximately three- to four-fold higher compared to the untreated group. Here, DMC represented a compound-induced apoptosis for cell death in the HeLa cervical cancer cell line. Our findings suggest that DMC, a phytochemical agent, is a potential candidate for antiproliferative cervical cancer drug development.
... Cisplatin, another chemotherapeutic agent, is used clinically for the cancer treatments. It targets deoxyribonucleic acid (DNA) replication and interferes the cell proliferation in tumor cells, such as cervical, ovarian, testicular, lung, bladder head and neck cancers [36,37]. It was also found that it accumulates in the cell organelles and cytosol, such as lysosomes, mitochondria, endoplasmic reticulum, and nucleus, and leads the cell to death in tumor cells. ...
We aimed to investigate the cytotoxicity of Metformin, Cisplatin, and Paclitaxel on MFE-319 endometrial carcinoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and immunocytochemistry assays. Half maximal inhibitory concentration (IC50) doses of three drugs alone and in the dual combinations were applied to the cells. Immunocytochemical method was performed for the cell survival and for phosphatidylinositol 3-kinase (PI3K), phosphorylated extracellular regulated kinases (pErk)-1/2, Akt-1, phosphorylated Akt (pAkt)-1/2/3 cell growth markers and angiogenic vascular endothelial growth factor (VEGF). Immunoreactivities were evaluated using H-score and analyzed using the one-way analysis of variance (ANOVA) test for statistics. It was found that these drugs caused a decrease in the immunoreactivities of these markers. Particularly, dual combination of Paclitaxel and Cisplatin decreased the immunoreactivities of PI3K, pErk-1/2, Akt-1, and pAkt-1/2/3. Cisplatin and Paclitaxel were more effective than Metformin; on the other hand, Metformin has been shown to enhance the efficacy of these two drugs. In vitro or in vivo further studies are needed to investigate the efficacy of these three drugs via PI3K/Akt signal pathway.
... Cisplatin-resistant lung cancer cells have higher levels of glutamate cysteine ligase (GCL), which is the first enzyme of the GSH biosynthetic pathway, and, consequently, elevated GSH. The increased GSH production is thought to counteract the higher levels of reactive oxygen species (ROS) induced by common chemotherapeutic drugs such as cisplatin, and, thereby, protects the cancer cells from oxidative damage [60,61]. Consistent with this, blocking glutamate flux using riluzole was able to selectively kill cisplatin-resistant cells in-vitro and in-vivo [62], and inhibition of GSH biosynthesis with buthionine sulfoximine was found to synergise with cisplatin in breast cancer in-vitro and in-vivo [63]. ...
Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.
... Subsequently, cisplatin inhibits DNA replication and induces apoptosis of cancer cells [29,30]. As a broad-spectrum antineoplastic drug, cisplatin is commonly used for the treatment of multiple malignant cancers including HCC [31][32][33]. However, the population of CD133 positive HCC cells showed significant resistance to cisplatin and is responsible for the failure of cisplatin treatment [34]. ...
The population of CD133 positive cancer cells has been reported to be responsible for drug resistance of hepatocellular carcinoma (HCC). However, the potential molecular mechanism by which CD133+ HCC cells develop drug resistance is still unclear. In this study, we found that CD133+ HepG2 and Huh7 cells were resistant to cisplatin treatment, compared to the CD133- HepG2 and Huh7 cells. However, treatment with osthole, a natural coumarin isolated from umbelliferae plant monomers, was found to resensitize CD133+ HepG2 and Huh7 cells to cisplatin treatment. In the mechanism research, we found that treatment with osthole increased the expression of PTEN. As a result, osthole inhibited the phosphorylation of AKT and Bad to decrease the amount of free Bcl-2 in CD133+ HepG2 and Huh7 cells. Finally, cisplatin-induced mitochondrial apoptosis was expanded. In conclusion, combination treatment with osthole can resensitize CD133+ HCC cells to cisplatin treatment via the PTEN/AKT pathway.
... Cisplatin, another chemotherapeutic agent, is used clinically for the cancer treatments. It targets deoxyribonucleic acid (DNA) replication and interferes the cell proliferation in tumor cells, such as cervical, ovarian, testicular, lung, bladder head and neck cancers [36,37]. It was also found that it accumulates in the cell organelles and cytosol, such as lysosomes, mitochondria, endoplasmic reticulum, and nucleus, and leads the cell to death in tumor cells. ...
We aimed to investigate the cytotoxicity of Metformin, Cisplatin, and Paclitaxel on MFE-319 endometrial carcinoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and immunocytochemistry assays. Half maximal inhibitory concentration (IC50) doses of three drugs alone and in the dual combinations were applied to the cells. Immunocytochemical method was performed for the cell survival and for phosphatidylinositol 3-kinase (PI3K), phosphorylated extracellular regulated kinases (pErk)-1∕2, Akt-1, phosphorylated Akt (pAkt)-1∕2∕3 cell growth markers and angiogenic vascular endothelial growth factor (VEGF). Immunoreactivities were evaluated using H-score and analyzed using the one-way analysis of variance (ANOVA) test for statistics. It was found that these drugs caused a decrease in the immunoreactivities of these markers. Particularly, dual combination of Paclitaxel and Cisplatin decreased the immunoreactivities of PI3K, pErk-1∕2, Akt-1, and pAkt-1∕2∕3. Cisplatin and Paclitaxel were more effective than Metformin; on the other hand, Metformin has been shown to enhance the efficacy of these two drugs. In vitro or in vivo further studies are needed to investigate the efficacy of these three drugs via PI3K∕Akt signal pathway.
... Platinum drugs are widely used in the treatment of different tumors, three of these compounds are approved by the United States Food and Drug Administration: cisplatin, carboplatin and oxaliplatin (7). Platinum drugs enter the cell through diffusion or by plasma membrane-mediated transporters (CTR1), usually allowing copper influx (8), by binding to methionine, histidine or cysteine CTR1 residues (9) to act as enzyme cofactor (10). Once inside the cell, platinum drugs bind to proteins, reduced Glutathione (GSH), and DNA N-7 site of purines (11). ...
... Platinum drugs are an effective way to treat cancer, however, drug resistance may hinder therapy (14). Resistance to platinum drugs could develop through several mechanisms: decreased drug entry into the cell, increased expulsion (8,11), increased detoxification (15,16), increased DNA repair pathways (12,17), upregulation of anti-apoptotic proteins such as Bcl-2, Bcl-XL, MCL-1(11), among others. Alternatively, epithelial mesenchymal transition (EMT) accompanies the development of drug resistance, with several molecules associated with EMT, such as transcription factors (Snail, Twist) and miRNAs (miRNA-200 family, miR-15, miR-186, etc.), being recognized as important for drug resistance (18) with effect in diverse signaling pathways associated with epithelial-mesenchymal transition such as STAT3, Notch, SMAD (19). ...
... In addition, DNA methylation of tumor suppressor genes and histone modifications are important resistance mechanisms (20). Finally, recent investigations associate epigenetic regulations as potential resistance mechanisms (21), with cisplatin resistance regulated by microRNAs and methylation/demethylation of genes such as FANCF in ovarian cancer, and related to cytokines/chemokines (axis CXCL12-CXCR4) (8) to be studied in detail later in the review. Examples of reported tumors developing resistance to cisplatin are ovarian cancer (22,23) usually developed during treatment (acquired resistance) (24), cervical (25,26), lung (27,28), and gastric cancer (29,30); the last two can also develop intrinsic resistance, occurring when the drug is ineffective from the beginning of treatment (14,31). ...
Cancer is a significant medical issue, being one of the main causes of mortality around the world. The therapies for this pathology depend on the stage in which the cancer is found, but it is usually diagnosed at an advanced stage in which the treatment is chemotherapy. Platinum drugs are among the most commonly used in therapy, unfortunately, one of the main obstacles to this treatment is the development of chemoresistance, which is the ability of cancer cells to evade the effects of drugs. Although some molecular mechanisms involved in resistance to platinum drugs are described, elucidation is still required of others. Secretion of inflammatory mediators such as cytokines and chemokines, by tumor microenvironment components or tumor cells, show direct influence on proliferation, metastasis and progression of cancer and are related to chemoresistance and poor prognosis. In this review, the general mechanisms associated with resistance to platinum drugs, inflammation on cancer development and chemoresistance in various types of cancer will be approached with special emphasis on the current history of CC chemokines subfamily-mediated chemoresistance.
... Platinum-based compounds have been the most actively used front-line clinical drug for the treatment of ovarian cancer for decades. The prognosis of patients with ovarian cancer can be defined by the response of the tumor to cisplatin; patients whose tumors are intrinsically resistant to platinum at the time of initial treatment or acquire resistance during treatment have very poor prognosis (1)(2)(3). Therefore, understanding of the crucial factors driving platinum resistance is needed to enhance the therapeutic outcomes of platinum-based chemotherapy. ...
Purpose:
Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. The goal of our study is to decipher the mechanism by which a metabolic kinase, diacylglycerol kinase alpha (DGKA), confers platinum resistance in ovarian cancer.
Experimental design:
Metabolic kinase RNAi synthetic lethal screening was used to identify a cisplatin resistance driver in ovarian cancer. DGKA variants were used to demonstrate the need for DGKA activity in cisplatin resistance. Phospho-proteomic and genomic screens were performed to identify downstream effectors of DGKA. Therapeutic efficacy of targeting DGKA was confirmed and clinical relevance of DGKA signaling was validated using ovarian cancer patient-derived tumors that had different responses to platinum-based therapy.
Results:
We found that platinum resistance was mediated by DGKA and its product, phosphatidic acid (PA), in ovarian cancer. Proteomic and genomic screens revealed that DGKA activates the transcription factor c-JUN and consequently enhances expression of a cell cycle regulator, WEE1. Mechanistically, PA facilitates JNK recruitment to c-JUN and its nuclear localization, leading to c-JUN activation upon cisplatin exposure. Pharmacological inhibition of DGKA sensitized ovarian cancer cells to cisplatin treatment and DGKA-c-JUN-WEE1 signaling positively correlated with platinum resistance in tumors derived from ovarian cancer patients.
Conclusions:
Our study demonstrates how the DGKA-derived lipid messenger, PA, contributes to cisplatin resistance by intertwining with kinase and transcription networks, and provides preclinical evidence for targeting DGKA as a new strategy in ovarian cancer treatment to battle cisplatin resistance.
... Cis-diamminedichloroplatinum (II) (cisplatin, CDDP), due to its broad spectrum of clinical activity and high efficacy, is one of the most extensively used chemotherapeutic drug and anticancer agent for treatment of numerous solid tumors [1][2][3], including testicular cancer [4], ovarian cancer [5], breast cancer [6], cervical cancer [7], non-small cell lung cancer [8], head and neck cancer [9], bladder cancer [10] and others [1,3,11]. Anticancer activity of CDDP has also been demonstrated when it is used in combination with other types of anticancer therapy, including radiotherapy [12], chemotherapy [13] or immunotherapy [3,14]. ...
Magnoflorine is an aporphine alkaloid present in plant species belonging to the Berberidaceae, Magnoliaceae, Menispermaceae, or Papaveraceae botanical families. The interest of magnoflorine has increased recently due to its multiplicity of pharmacological properties. The aim of this study was the analysis of combined anti-proliferative effect of magnoflorine and cisplatin and the assessment of drug-drug pharmacological interaction between these agents using isobolographic method in MDA-MB-468 human breast, NCIH1299 lung, TE671 rhabdomyosarcoma, or T98G glioblastoma cancer cell lines. Magnoflorine in combination with cisplatin at a fixed ratio of 1:1 augmented their anticancer action and yielded synergistic or additive pharmacological interactions by means of isobolographic method, therefore combined therapy using these two active agents can be a promising chemotherapy regimen in the treatment of some types of breast, lung, rhabdomyosarcoma, and glioblastoma cancers.
