Platinum-based Antitumor Drugs Research Articles

Progress in the study of reproductive toxicity of platinum-based antitumor drugs and their means of prevention.

Platinum-based antitumor drugs are broad-spectrum agents with unique mechanisms of action. Combination chemotherapy regimens based on platinum drugs are commonly used in cancer treatment. However, these drugs can cause various adverse reactions in the human body through different routes of administration, including reproductive toxicity, genetic toxicity, and embryonic developmental toxicity. Preventing adverse effects is crucial to enhance patients' quality of life and reduce healthcare costs. This article discusses the types and developmental history of antitumor active platinum compounds, their mechanisms of action, routes of administration, and their potential reproductive, genetic, and embryonic developmental toxicity. This text explores preventive measures based on animal experimental results. Its aim is to provide references for personalized treatment and occupational protection when using platinum drugs. The continuous progress of science and technology, along with the deepening of medical research, suggests that the application of platinum drugs will broaden. Therefore, the development of new platinum drugs will be an important direction for future research.

Lysosome-targeted ruthenium(II) complex encapsulated with pluronic® F-127 induces oncosis in A549 cells.

Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic® F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.

Anlotinib hydrochloride combined with tislelizumab, paclitaxel liposome, and nedaplatin regimen for preoperative neoadjuvant therapy of esophageal cancer: A single-arm, single-center, phase II exploratory clinical study.

e16082 Background: Local recurrence and distant metastasis are important causes of high mortality in patients with locally advanced esophageal cancer. Neoadjuvant therapy combined with surgery can significantly improve the prognosis of patients with locally advanced esophageal cancer. Based on the clinical data of anlotinib (a multi-targeted tyrosine kinase inhibitors) and tislelizumab (anti-pd-1 antibodies), paclitaxel liposome (a cytotoxic anti-tumor drugs) and nedaplatin (a platinum-based anti-tumor drugs) in patients with esophageal cancer, to evaluate the efficacy and safety of anlotinib hydrochloride combined with tislelizumab, paclitaxel liposome and nedaplatin in preoperative neoadjuvant therapy for patients with stage IIB-IVA esophageal cancer. Methods: This study included 18-75 years old, ECOG PS 0-1 patients with potentially resectable stage IIB-IVA esophageal cancer with a predicted survival time of ≥12 weeks and confirmed by histopathology or cytology. Patients who met the inclusion criteria received anlotinib (oral, 12mg/d1-14,Q3W) combined with tislelizumab (intravenous drip, 200mg/d1,Q3W), paclitaxel liposome (intravenous drip, 175mg/m2/d1,Q3W) and nedaplatin (intravenous drip, 80mg/m2/d1,Q3W). After 2 cycles of neoadjuvant therapy, surgery was performed, and 4-6 weeks of chemotherapy combined with targeted immune adjuvant therapy was performed after the operation, and then Anlotinib combined with tislelizumab targeted immune maintenance therapy was performed until the disease progressed. Subjects who failed to complete at least one cycle of clinical trials according to this program due to non-experimental drug factors, and seriously violated this research program, such as: failure to follow the prescribed dose, method and course of medication, will be excluded from this study. The primary endpoint was objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), R0 resection rate, and pathological complete response rate. Results: From October 2021 to February 2023, 38 patients were included in this study, and clinical data of 27 patients can be used to track and evaluate clinical efficacy. The median age of the subjects was 58.5 years (range 47-75 years). the primary study end point was an ORR of 77.8% (95% CI，61%-94.5%). Conclusions: We will strictly implement the research protocol and objectively evaluate the anti-tumor activity and safety of anlotinib hydrochloride combined with tislelizumab, paclitaxel liposome and nedaplatin regimen in the treatment of patients with stage IIB ~ IVA esophageal cancer. In order to provide a safe and reliable neoadjuvant therapy for patients with locally advanced esophageal cancer. Clinical trial information: ChiCTR2100049693 .

Synthesis, characterization, and biological activity of sterically hindered fluorine-containing platinum(II) complexes

Picoplatin is a sterically hindered antitumor compound with unique chemical and DNA binding properties, but its curative effect is not as good as other platinum drugs. Therefore, a series of sterically hindered fluorine-containing platinum(II) complexes Y1–Y5 were synthesized and characterized by introducing fluorine atoms at the 2-position of the pyridine group and different leaving group ligands. In vitro antiproliferative activity assessments of these complexes have been performed against A549, MCF-7, SW480, HCT116, HepG2 human cancer cell lines, and LO2 normal cells. The results showed that Y1 with 2-fluoropyridine coordination and chloride ion as the leaving group exhibited stronger antiproliferative activity and selectivity in the tested cancer cell lines, especially for A549 cancer cells. DNA binding constants were determined by UV absorption and fluorescence titration, and the binding ability of Y1 to DNA is much stronger than that of the others, which shows Y1 has better DNA damage ability. For the determination of apoptosis by the complex, the results were consistent with those of the MTT assay, and the apoptosis rate of Y1 reached 38.9%. Therefore, our work offers an advantageous method for the development of new platinum-based antitumor drugs.

Molecular dynamics simulation study of DNA conformation changes caused by the dinuclear platinum(II) complexes with the bisphosphonate group

Bisphosphonate (BP) has been widely used as a bone-targeting group, and the BP-modified platinum(II) complexes have shown potential to as anticancer drugs against bone-related diseases, such as osteosarcoma. DNA conformation changes induced by the BP-modified dinuclear platinum(II) complexes have been investigated using molecular dynamics simulations. The results indicated that the BP-modified dinuclear platinum(II) complexes coordinated to DNA results in DNA structural distortions, including twisting, unwinding and bending. Furthermore, the rigidity of the bridging linkers in the BP-modified platinum(II) complex may induce more significant DNA structural distortions with same spans. The results provide the detail information of DNA conformational changes induced by the BP-modified platinum(II) complexes with different flexibility of bridging linkers, and are helpful for exploring novel platinum-based antitumor drugs.

The ruthenium complex assists in nuclear targeting and selective killing of tumor cells.

In clinical studies, the toxicity of platinum-based antitumor drugs limits their use. DNA is the most widely studied target of metal-based complexes. Thus, nuclear targeting and selective killing have become the purpose of ruthenium complex design. We synthesized a carboline derivative and its ruthenium complex, NBD and NBD-Ru, and characterized their properties. UV spectra were used to monitor their stability. Transmission electron microscopy and dynamic light scattering were used to identify the self-assembly properties. Inductively coupled plasma mass spectrometry was used to assay the distribution of the Ru complexes in cells with or without transferrin. Besides, the tumor cell killing activities with or without transferrin were detected by MTT assay. An imaging flow cytometer was applied to observe the fluorescence further to identify the cellular distribution. The effects of NBD and NBD-Ru on DNA and the cell cycle were also measured. In vivo, the antitumor and antimetastatic activities of NBD and NBD-Ru were assessed in S180 and LLC tumor-bearing mice. We found that introducing Ru improved the solubility and stability, enabling NBD-Ru to self-assemble into nanoparticles with the EPR effect. At the same time, binding affinity with transferrin increased significantly after complexation, meaning NBD-Ru could target and selectively kill tumors via Tf/TfR pathway. More interestingly, ruthenium assisted the complex in achieving nuclear penetration, which can kill tumor cells by interacting with DNA. In vivo experiments further verified our conclusion in vitro. NBD-Ru could inhibit not only the growth of a primary tumor but also lung metastasis, which was related to the killing effect of the complex on tumor cells (Ki67) and inhibition of neovascularization (CD31). At the same time, the systemic toxicity of the ruthenium complex in vivo was reduced because of the targeting effect, and the biosafety was improved. In conclusion, we found that ruthenium assisted in nuclear targeting and selective killing in vitro and in vivo.

Novel cis-Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action.

One concept of improving anticancer effects of conventional platinum-based antitumor drugs consists of conjugating these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, physicochemical characterization, biological effects, and mechanisms of action of four new analogs of conventional cisplatin, namely, cis-Pt(II) complexes containing either methyl or ethyl pyrazole N-donor ligands and chlorido or iodido ligands. It is noteworthy that while chlorido complexes display activity in a variety of cancer cell lines comparable to cisplatin, iodido complexes are considerably more potent due to their enhanced hydrophobicity and consequently enhanced cellular accumulation. Moreover, all of the studied Pt(II) alkylpyrazole complexes display a higher selectivity for tumor cells and effectively overcome the acquired resistance to cisplatin. Further results focused on the mechanism of action of the studied complexes and showed that in contrast to cisplatin and several platinum-based antitumor drugs, DNA damage by the investigated Pt(II)-alkylpyrazole complexes does not play a major role in their mechanism of action. Our findings demonstrate that inhibition of the tubulin kinesin Eg5, which is essential for forming a functional mitotic spindle, plays an important role in their mechanism of antiproliferative action.

Assessing Impact of Platinum Complexes on Mitochondrial Functions.

Platinum-based antitumor drugs play important roles in the clinical treatment of various tumors. Nevertheless, some deficiencies such as poor targeting ability, low bioavailability, in vivo deactivation, drug resistance, and side effects undermine the efficacy of these drugs. Mitochondria are important organelles which regulate the energy metabolism, physiological function, life span, and survival of the cells. Regulating or interfering with mitochondrial metabolism is of great significance in the prevention or treatment of cancers. Thus, a series of mitochondrion-targeted platinum complexes were prepared by modifying triphenylphosphine (TPP+) through chemical modifications, which endow traditional platinum drugs with new properties and mechanisms through interfering with mitochondrial DNA (mtDNA), mitochondrial membrane potential (MMP), mitochondrial morphology, mitochondrial bioenergetics, or production of reactive oxygen species (ROS), thereby opening a new path for the clinical application of platinum drugs. Here we introduce the synthesis of some TPP+-modified platinum (II, IV) complexes in details and the detection method of the activity parameters related to the mitochondrial functions.

Novel ruthenium and palladium complexes as potential anticancer molecules on SCLC and NSCLC cell lines

Lung cancer is one of the major causes of cancer-related deaths in the world. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, and small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Proper therapies for SCLC have not yet been developed. However, new molecules have been designed and big innovation in treating SCLC has been achieved. Platinum-based antitumor drugs like cisplatin and carboplatin have several disadvantages including side effects, cisplatin-resistant tumors and limited solubility in aqueous media. Thus, two novel chiral aminoalcohol-based bis(phosphinite) ligands containing (η6-p-cymene)-Ru(II)-phosphinite and bis(phosphinite)–Pd(II) complexes were synthesized and evaluated for anticancer activity. In this study, the results showed that complex 1 has the strongest cytotoxic effects on SCLC and NSCLC cell lines. On the other hand, cisplatin, ruthenium and palladium complexes are capable to induce apoptosis. Especially, complexes 1 and 2 can induce apoptosis for both SCLC and NSCLC. When compared to the qRT-PCR and TUNEL results, we obtained a significant correlation between apoptotic index and p21, Bax gene expressions. This work revealed the potential of the synthesized complexes as anticancer agents with cytotoxic and pro-apoptotic activity as leading compounds for further anticancer researches.

Platinum-Based Antitumor Drugs and Their Liposomal Formulations in Clinical Trials

Platinum-based antitumor drugs are the most common drugs in modern oncology practice. They are used for the treatment of a large number of malignant tumors of different etiology. However, their low specificity and high systemic toxicity significantly reduce the efficacy of chemotherapy. With the goal of improving pharmacological properties of platinum-based drugs, an intense search for supramolecular drug delivery systems is being carried out in many laboratories. This review focuses on liposomal drugs, which are currently at different stages of clinical trials. In the first part of the review we described modern concepts on the action of Pt-based drugs. Information about the drugs used in clinical practice as well as data about some new promising compounds is also provided. Also, justification of the rationale for the creation of liposomal drug delivery systems is given, and six Pt-containing liposomal formulations under clinical trials are reviewed, including the published data on the composition, how they act, and the results of preclinical and clinical trials. Several examples of new Pt-based liposomal formulations are given. The prospects of the liposomal platform development for platinum-based drugs are discussed.

Abstract A16: Evaluation of the genotoxicity of ruthenium complex, trans-[Ru(ThySMet)(PPh3)2(bipy)]PF6, by comet assay in vitro on breast cells and in vivo

Abstract Cancer remains a major public health problem, accounting for one in six deaths worldwide. One of the most common types of cancer in women is breast cancer, which is extremely heterogeneous and composed of different subtypes. The majority of drugs currently used in cancer treatment show no selectivity for tumor cells, provoking undesired side effects. Cisplatin, discovered more than 40 years ago, and successive generations of platinum-based antitumor drugs have demonstrated that metal complexes may play an important role in the cancer treatment. Metals have unique characteristics that can be exploited by the chemistry coordination for the design of new drugs with fewer side effects. In the last two decades, ruthenium complexes have been widely studied and gained prominence for cancer treatment due to their unique characteristics, such as high rate of ligand exchange, accessible oxidation states, and the ability to mimic the iron to bind biologic molecules. This study aimed to evaluate the genotoxicity effects of the ruthenium complex trans-[Ru(ThySMet)(PPh3)2(bipy)]PF6 in vitro and in vivo by the comet assay, which can be used to measure DNA damage in individual eukaryotic cells. Briefly, for in vitro assays, MDA-MB-231 malignant breast cells and MCF-10A nonmalignant breast cells were seeded (1x105/1000µL) into sterile 12-well plates. Cells were allowed to grow at 37°C in 5% CO2 for 24h and then treated or not (control) with different concentrations (2, 4 or 8µM) of the ruthenium complex or positive control cisplatin (8µM) for 1h. After this period, cells were harvested, centrifuged and resuspended in 500μL of culture medium. For in vivo assays, the animals, swiss mice, were kept in a climate-controlled environment (22±2°C) with a 12/12h light/dark cycle and food and water ad libitum. The Animal Bioethics Committee (CEUA/UNESP FAMEMA, Marília, São Paulo, Brazil) approved this study (protocol no. 828/2016). Mice were divided into five groups with five animals in each group. The ruthenium complex (12.5, 25 or 50mg/kg), positive control doxorubicin (20mg/kg), or negative control (vehicle - DMSO) were administered intraperitoneally for 3 days at 24h interval. On the third day, peripheral blood from the tail vein was collected after 4h after the administration of the last treatment. Then both, cell suspension or blood, were mixed with 120µL of 0.5% low-melting point agarose and dropped on slides precoated with 1.5% normal melting point agarose and taken to a lysis solution for 1h. After denaturation (20min) and alkaline electrophoresis (25V, 300mA, 20min) the slides were neutralized and fixed. The slide staining was performed with GelRed® (Uniscience) and comet analysis of at least 150 random cells per group was done visually according to comet tail size using a fluorescence microscope (Olympus BX61-TRF5). In vitro results of genotoxic evaluation of trans-[Ru(ThySMet)(PPh3)2(bipy)]PF6 demonstrate that this complex was able to induce significant DNA damage in MDA-MB-231 cells at the highest concentrations (4 and 8μM), as well as the positive control, cisplatin (8μM). However, the complex did not cause DNA damage in MCF-10A cells; only cisplatin induced damage to these cells. The results of genotoxic evaluation of in vivo assays indicated that only the group of animals treated with the highest dose of the complex (50mg/kg) and the animals treated with doxorubicin presented DNA damage. These results demonstrate that this complex causes DNA damages in vitro with more specificity for tumor cells and that only in the highest dose it causes DNA damages in vivo. Therefore, more studies should be performed to evaluate its potential for breast cancer treatment. Citation Format: Amanda Blanque Becceneri, Cecília Patrícia Popolin, Ana Maria Plutin, Edson Luis Maistro, Alzir Azevedo Batista, Márcia Regina Cominetti. Evaluation of the genotoxicity of ruthenium complex, trans-[Ru(ThySMet)(PPh3)2(bipy)]PF6, by comet assay in vitro on breast cells and in vivo [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A16.

Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis.

Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting—carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively—cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. hCtr1 expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates hCtr1. Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy.

Interaction between carboplatin and cucurbit[7]uril studied by means of multinuclear NMR spectroscopy and DFT calculations

Encapsulation of platinum-based antitumor drugs into host molecules is a rapidly growing field, as it provides the potential to reduce the toxicity and overcome tumor resistance issues, with cucurbit[n]uril family being a very promising class of potential hosts. Although, previously it was reported that carboplatin, a second generation platinum-based antitumor drug, did not interact with cucurbit[7]uril, in this work, we have observed such an interaction by means of multinuclear NMR spectroscopy. Apparently, upon the interaction with cucurbit[7]uril in aqueous solution, carboplatin decomposes into 1,1-cyclobutane dicarboxylic acid and some cis-PtL2(NH3)2 (L = H2O or OH−) which forms a relatively stable inclusion complex with cucurbit[7]uril. DFT calculations of the geometry of hypothetical complexes and NMR shielding of 1H, 13C, and 195Pt nuclei help with interpretation of the experimental NMR results.

Acute cold allodynia induced by oxaliplatin is attenuated by amitriptyline

Oxaliplatin is a third-generation, platinum-based antitumor drug used to treat colorectal cancer. Since its main adverse effect is neuropathic pain resulting from chemotherapy‑induced peripheral neuropathy (CIPN), this drug is used to study the neurobiology of CIPN in rodents and to search for analgesics that could attenuate neuropathic pain symptoms - cold and tactile allodynia that develop in most of the oxaliplatin‑treated subjects. In this research, testing across various temperatures, we assessed the cold reactivity threshold of albino Swiss mice treated with oxaliplatin. We also investigated if amitriptyline, a tricyclic antidepressant drug and a sodium channel inhibitor, could attenuate cold allodynia caused by this chemotherapeutic drug. Cold allodynia was induced using a single intraperitoneal dose of oxaliplatin. In the cold plate test while testing various temperatures the pain sensitivity threshold was assessed at different time-points after oxaliplatin (late‑phase allodynia). Antiallodynic activity of intraperitoneal amitriptyline was assessed for doses of 1, 2.5 and 10 mg/kg. A statistically significant decrease in latency time to pain reaction was detected for all temperatures applied, but the earliest response (i.e., 2 h post‑injection) was noted at 2.5°C. In all experimental groups early‑phase cold allodynia was fully developed 3 h after oxaliplatin injection and it was maintained until the end of the observation period (7 days). Early‑phase cold allodynia induced by oxaliplatin can be effectively attenuated by amitriptyline.

Amino-functionalized nano-vesicles for enhanced anticancer efficacy and reduced myelotoxicity of carboplatin

Carboplatin is one of the few platinum-based antitumor drugs used worldwide. Unfortunately, systemic carboplatin therapy is limited by its dose-related myelosuppression. In this study, a viable way to reduce the serious myelotoxicity of carboplatin while improving its therapeutic efficacy using amino-functionalized polyphosphazene vesicles is reported. First, three polyphosphazenes with different amino content were synthesized by amidating hydrophobic side groups; these polyphosphazenes could self-assemble into polymersomes with similar particle size and morphology. Based on FTIR analysis, hydrogen bonding interactions between the polymeric carriers and carboplatin were validated and shown to predominantly contribute to the significant improvement of drug loading in polymersomes. Therefore, it turned out that the amino level of polymers played a substantial role in carboplatin encapsulation. Then, PEAP-2-C polymersomes were optimized for further experimental verification to achieve depressed carboplatin-induced myelotoxicity as well as promote curative effects against CT-26 colon adenocarcinoma. These results in vitro and in vivo proved that amino-functionalized polyphosphazene vesicles have great potential for carboplatin delivery in the application of cancer therapy.

Mass Spectrometry Based Proteomics Study of Cisplatin-Induced DNA-Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells.

Platinum-based antitumor drugs such as 1,1,2,2-cis-diamminedichloroplatinum(II) (cisplatin), carboplatin, and oxaliplatin are currently used to treat nearly 50% of all cancer cases, and novel platinum based agents are under development. The antitumor effects of cisplatin and other platinum compounds are attributed to their ability to induce interstrand DNA-DNA cross-links, which are thought to inhibit tumor cell growth by blocking DNA replication and/or preventing transcription. However, platinum agents also induce significant numbers of unusually bulky and helix-distorting DNA-protein cross-links (DPCs), which are poorly characterized because of their unusual complexity. We and others have previously shown that DPCs block DNA replication and transcription and causes toxicity in human cells, potentially contributing to the biological effects of platinum agents. In the present work, we have undertaken a system-wide investigation of cisplatin-mediated DNA-protein cross-linking in human fibrosarcoma (HT1080) cells using mass spectrometry-based proteomics. DPCs were isolated from cisplatin-treated cells using a modified phenol/chloroform DNA extraction in the presence of protease inhibitors. Proteins were released from DNA strands and identified by mass spectrometry-based proteomics and immunological detection. Over 250 nuclear proteins captured on chromosomal DNA following treatment with cisplatin were identified, including high mobility group (HMG) proteins, histone proteins, and elongation factors. To reveal the exact molecular structures of cisplatin-mediated DPCs, isotope dilution HPLC-ESI+-MS/MS was employed to detect 1,1-cis-diammine-2-(5-amino-5-carboxypentyl)amino-2-(2'-deoxyguanosine-7-yl)-platinum(II) (dG-Pt-Lys) conjugates between the N7 guanine of DNA and the ε-amino group of lysine. Our results demonstrate that therapeutic levels of cisplatin induce a wide range of DPC lesions, which likely contribute to both target and off target effects of this clinically important drug.

Palladium complexes: new candidates for anti-cancer drugs

Platinum complexes which are most studied metal complexes due to their importance as adjuvant therapy of cancers aiming to induce tumor-cell-death. Some of the platinum-based antitumor drugs like cisplatin, carboplatin and oxaliplatin, have several disadvantages including side effects, cisplatin-resistant tumors, limited solubility in aqueous media, and so on. Thus, to achieve lower undesirable toxicity, enhanced solubility, and tumor selectivity, significant amount of work have been devoted to the preparation of modified platinum complexes. One of the ways to design the new anti-tumor agents related to cisplatin is to change the nature of central metal ion. Among the non-platinum metal complexes studied for cancer treatment, palladium(II) derivatives were readily chosen due to their structural analogy with those containing Pt(II) complexes. This review focuses on anti-tumor property of Pd(II) complexes and makes comparisons with similar property of cisplatin. Then, in the review, palladium(II) complexes have been classified according to their leaving ligands into palladium(II) complexes. In the last part, the most important factors affecting on the anti-tumor activity of the Pd(II) complexes were discussed. These factors are encouraging more researches in this field, for future applications.

Transport of platinum bonded nucleotides into proteoliposomes, mediated by Drosophila melanogaster thiamine pyrophosphate carrier protein (DmTpc1)

The results of the present study suggest that DmTpc1 is actively implicated in the specific uptake of free cytoplasmic Pt bonded nucleotides, and therefore could be linked to the mechanism of action of some platinum-based antitumor drugs. Although DmTpc1 has a low affinity for model [Pt(dien)(N7-5′-dGTP)] and cis-[Pt(NH3)2(py)(N7-5′-dGTP)] compared to dATP it's well known that DNA platination level of few metal atoms per double-stranded molecule may account for the pharmacological activity of platinum based antitumor drugs. This is the first investigation where it has been demonstrated that a mitochondrial carrier is directly involved in the transport of metalated purines related with the cisplatin mechanism of action. Moreover it is shown as a lower hindrance of nucleotide bonded platinum complexes could strongly enhance mitochondrial uptake. Furthermore, a new application of ICP-AES addressed to measure the transport of metalated nucleobases, by using a recombinant protein reconstituted into liposomes, has been here, for the first time, developed and compared with a standard technique such as the liquid scintillation counting.

Antineoplastic Activities, Apoptotic Mechanism of Action and Structural Properties of a Novel Silver(I) Chelate

In a previous work, the author has investigated the antimicrobial and cytotoxic properties of tartaric and glutamic acids silver(I) chelates. In a following work, the author has reported on the in vitro cytotoxicity and the mechanism of action of a silver(I) tartaric acid chelate synthesized by the author given the title name Aliargentumycine (AAgM) on hematopoietic malignancies. The in vitro antineoplastic activities of AAgM on solid human breast ductal carcinoma (T- 47D) and disseminated T-cell acute lymphoblastic leukemia (Jurkat) cell lines, its mechanism of action and its structural properties were investigated here. The cytotoxicity results of AAgM were compared to cisplatin, a ubiquitously used platinum-based antitumor drug. Results have indicated that AAgM demonstrated excellent cytotoxicity on both tumor cell lines studied when compared to cis-platin, especially for T-47D. Unlike cisplatin, AAgM was found to exhibit an aberrant triphasic cytotoxicity profile. Phase I exhibited cytotoxicity in the nanoconcentration range, Phase II exhibited no cytotoxicity in the intermediate range, and finally Phase III exhibited cytotoxicity in the microconcentration range. Phase II lacks of cytotoxicity might be an indication of cells reverting back to being nonmalignant in a similar way to 5-Aza-2'- deoxycytidine (decitabine). Quantitative pharmacokinetic-pharmacodynamic analyses were undertaken and were found that AAgM induced significantly better cytotoxic activities than cisplatin between 1.9-30.5 ng/mL while cisplatin did not exhibit any cytotoxicity on T-47D below 122 ng/mL. TUNEL assay was performed and AAgM was found to elicit its antineoplastic activities by apoptosis. X-ray diffraction showed that AAgM is a polymeric chain hydrate structure with no imposed symmetry and the complex around the silver is a monohydrate distorted skew trapezoidal bipyramidal sixcoordinate. AAgM is composed of lipophilic and hydrophilic moieties, making AAgM miscible in both lipids via the tartrate rings and ionic solutions via the water molecules. The results are expected to have significant implications on cancer therapy, especially solid neoplasms, which are exceptionally difficult to treat, and those derived from epithelial and mesenchymal cells, which are not prone to apoptotic responses with cdk inhibitor drugs. Also, the results should be very useful in the design of future novel silver-based antineoplastic drugs.

Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis

Dicycloplatin, a new supramolecular platinum-based antitumor drug, has been approved by the State Food and Administration (SFDA) of China. In this study, we investigated the anticancer activity of dicycloplatin in cancer cells and signaling pathways involved in dicycloplatin-induced apoptosis. Dicycloplatin inhibited the proliferation of cancer cells and increased the percentage of apoptosis in a concentration-dependent manner. Besides, some apoptosis related events were observed after treatment with dicycloplatin, including increase of reactive oxygen species (ROS), collapse of mitochondrial membrane potential (Δψm), release of cytochrome c from the mitochondria to the cytosol, upregulation of p53, which were accompanied by activation of caspase-9, caspase-3, caspase-8, and poly (ADP-ribose) polymerase cleavage in a concentration-dependent manner. The role of apoptosis in dicycloplatin-mediated cell death was further confirmed by the concomitant treatment with caspase-8 or caspase-9 inhibitors, which inhibited apoptosis and PARP cleavage. Intracellular glutathione (GSH) was also found to inhibit the cytotoxic effect of dicycloplatin. In conclusion, these findings suggest that dicycloplatin induces apoptosis through ROS stress-mediated death receptor pathway and mitochondrial pathway which is similar to carboplatin.