Anticancer Research Articles

Bone Marrow Stromal Cells Enhance Differentiation of Acute Myeloid Leukemia Induced by Pyrimidine Synthesis Inhibitors.

Acute myeloid leukemia (AML) is a heterogeneous group of hematologic malignancies characterized by differentiation arrest, high relapse rates, and poor survival. The bone marrow (BM) microenvironment is recognized as a critical mediator of drug resistance and a primary site responsible for AML relapse. Our previous study reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induces AML cell differentiation by inhibiting pyrimidine synthesis and activating Checkpoint kinase 1. While the protective effect of BM stroma on leukemia cells in response to cytotoxic drugs is well-documented, its effect on AML differentiation remains less explored. In this study, we investigated the impact of stromal cell lines and primary mesenchymal stromal cells (MSCs) on AML cell line differentiation triggered by AICAr and brequinar, a known dihydroorotate dehydrogenase (DHODH) inhibitor. Our findings indicate that the mouse MS-5 stromal cell line, known for its cytoprotective effects, does not inhibit AML cell differentiation induced by pyrimidine synthesis inhibitors. Interestingly, AICAr caused morphological changes and growth arrest in MS-5 stromal cells via an AMPK-dependent pathway. Human stromal cell lines HS-5 and HS-27, as well as primary MSCs isolated from patient bone marrow, were superior in promoting AML differentiation compared to mouse cells in response to AICAr and brequinar, with the inhibitors not significantly affecting the stromal cells themselves. In conclusion, our study highlights the supportive role of human BM MSCs in enhancing the differentiation effects of pyrimidine synthesis inhibitors on AML cells, suggesting that AML treatment strategies focusing on differentiation rather than cell killing may be successful in clinical settings.

Human bone marrow mesenchymal stem cell-derived exosomes loaded with gemcitabine inhibit pancreatic cancer cell proliferation by enhancing apoptosis

BACKGROUND Pancreatic cancer remains one of the most lethal malignancies, and has limited effective treatment. Gemcitabine (GEM), a chemotherapeutic agent, is commonly used for clinical treatment of pancreatic cancer, but it has characteristics of low drug delivery efficiency and significant side effects. The study tested the hypothesis that human bone marrow mesenchymal stem cell (MSC)-derived exosomes loaded with GEM (Exo-GEM) would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis. AIM To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro . METHODS Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis. Exo-GEM through electroporation, sonication, or incubation, and the loading efficiency was evaluated. The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays. RESULTS The isolated exosomes had an average size of 76.7 nm. The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation. The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02 μM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells. Moreover, Exo-GEM enhanced the frequency of GEM-induced apoptosis in both cell lines. CONCLUSION Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis, offering a promising drug delivery system for improving therapeutic outcomes.

Hybrid Molecules Containing Methotrexate, Vitamin D, and Platinum Derivatives: Synthesis, Characterization, In VitroCytotoxicity, In Silico ADME Docking, Molecular Docking and Dynamics.

Designing hybrid-based drugs is one promising strategy for developing effective anticancer drugs that explore combination therapy to enhance treatment efficacy, overcome the development of drug resistance, and lower treatment duration. Bisphosphonates and Vitamin D are commonly administered drugs for the treatment of bone diseases and the prevention of bone metastases. Platinum-based and methotrexate are widely used anticancer drugs in clinics. However, their use is hampered by adverse side effects. Hybrid-based compounds containing either bisphosphonate, vitamin D, platinum-based or methotrexate were synthesized and characterized using FTIR, 1H-,31P, 13C-NMR, and UHPLC-HRMS which confirmed their successful synthesis. The hydroxyapatite bone binding assay revealed a promising percentage binding affinity of the bisphosphonate hybrid compounds. In vitro cytotoxicity assays on MCF-7 and HT-29 cell lines revealed a promising cytotoxic effect of hybrid 19 at 50 and 100 µg/mL on HT-29 and hybrid 15 on MCF-7 at 100 µg/mL. Molecular docking and dynamics simulation analysis revealed a binding affinity of -9.70 kcal/mol for hybrid 15 against Human 3 alpha-hydroxysteroid dehydrogenase type 3, showing its capability to inhibit Human 3 alpha-hydroxysteroid dehydrogenase type 3. The Swiss ADME, ProTox-II, GUSAR (General Unrestricted Structure-Activity Relationships), and molecular docking and dynamics studies revealed that these compounds are promising anticancer compounds.

Potentials of Beta-lactam and its Effective use as Anti-cancer and Anti-diabetic Drugs

Potentials of Beta-lactam and its Effective use as Anti-cancer and Anti-diabetic Drugs

A comprehensive review on microbial diversity and anticancer compounds derived from seaweed endophytes: a pharmacokinetic and pharmacodynamic approach.

Seaweed endophytes are a rich source of microbial diversity and bioactive compounds. This review provides a comprehensive analysis of the microbial diversity associated with seaweeds and their interaction between them. These diverse bacteria and fungi have distinct metabolic pathways, which result in the synthesis of bioactive compounds with potential applications in a variety of health fields. We examine many types of seaweed-associated microorganisms, their bioactive metabolites, and their potential role in cancer treatment using a comprehensive literature review. By incorporating recent findings, we hope to highlight the importance of seaweed endophytes as a prospective source of novel anticancer drugs and promote additional studies in this area. We also investigate the pharmacokinetic and pharmacodynamic profiles of these bioactive compounds because understanding their absorption, distribution, metabolism, excretion (ADMET), and toxicity profiles is critical for developing bioactive compounds with anticancer potential into effective cancer drugs. This knowledge ensures the safety and efficacy of proposed medications prior to clinical trials. This study not only provides promise for novel and more effective treatments for cancer with fewer side effects, but it also emphasizes the necessity of sustainable harvesting procedures and ethical considerations for protecting the delicate marine ecology during bioprospecting activities.

Discovery, lead identification and exploration of potential oxadiazole derivatives in targeting STAT3 as anti-cancer agents

Discovery, lead identification and exploration of potential oxadiazole derivatives in targeting STAT3 as anti-cancer agents

Combination of S-1 and the oral ATR inhibitor ceralasertib is effective against pancreatic cancer cells.

In our previous study, we found that the Chk1 inhibitor prexasertib enhances the antitumour effect of the oral anticancer drug S-1 against pancreatic cancer cells. In this study, we investigated the effect of combining S-1 and ceralasertib, an oral inhibitor of ATR, which is located upstream of Chk1. Ceralasertib is currently being investigated in multiple clinical trials for various cancers. The cell-proliferation inhibitory effect was measured by MTT assay, using the pancreatic cancer cell lines BxPC-3, SUIT-2, PANC-1, and MIA PaCa-2, while apoptosis was measured by flow cytometry using PI/Annexin staining. The mechanism underlying the combined effect was analysed using western blotting, and the antitumor effect was analysed using a mouse xenograft model. MTT assay revealed that the combination of S-1 and ceralasertib had a synergistic effect, leading to the suppression of cell proliferation. Measurement with PI/Annexin staining revealed that the combination of S-1 and ceralasertib induced apoptosis more efficiently than either drug alone. Western blotting results showed that ceralasertib inhibited S-1-induced activation of ATR and Chk1. The average estimated tumour volume after 3weeks of administration was 601 mm3 in the S-1 group, 580 mm3 in the ceralasertib group, and 298 mm3 in the combination group. The combination of S-1 and ceralasertib demonstrated a high antiproliferative effect in inhibiting tumour growth in vitro.

Oxindole–benzothiazole hybrids as CDK2 inhibitors and anticancer agents: design, synthesis and biological evaluation

In the current study, molecular hybridization between the oxindole core and benzothiazole system through an acetohydrazide moiety was accomplished for the design of a new series of oxindole–benzothiazole hybrids 9a–r targeting CDK2 for cancer therapy. The afforded hybrids displayed promising growth inhibitory activity on NCI cancer cell lines at 10 µM. Compound 9o displayed mean GI% = 55.91%. Based on the potent activity of 9o, it was further assessed for its cytotoxic activity at five dose level and it demonstrated GI50 reaching 2.02 µM. Analysis of the cell cycle of the prostate cancer cell line DU145 after treatment with 9o confirmed its ability to arrest its cell cycle at the G1 phase. Moreover, 9o proved its ability to potentiate the apoptosis and necrosis of the same cell line. Furthermore, the oxindole–benzothiazole hybrids 9b, 9f and 9o showed IC50 = 0.70, 0.20 and 0.21 µM, respectively on CDK2. Besides, molecular docking simulation of the synthesized oxindole–benzothiazole hybrid 9o proved the expected binding mode which involves the accommodation of the oxindole moiety in the ATP binding pocket where it is involved in hydrogen bonding and hydrophobic interactions with the essential amino acids in the hinge region while the benzothiazole moiety is oriented toward the solvent region. Investigation of the physicochemical properties of the hybrids 9a–r highlights their acceptable ADME properties that can be somewhat developed for the discovery of new anticancer agents.

Phytochemicals and Nanotechnology: A Powerful Combination against Breast Cancer.

Considerable advancements have been made in breast cancer therapeutics in the past few decades. However, the advent of chemo-resistance and adverse drug reactions coupled with tumor metastasis and recurrence posed a serious threat to combat this lethal disease. Novel anti-cancer agents, as well as new therapeutic strategies, are needed to complement conventional breast cancer therapies. The quest for developing novel anti-cancer drugs caused an upsurge in exploring and harnessing natural compounds, especially phytochemicals. Various research groups have explored and documented the anti-cancer potential of wide variety of phytochemical groups including flavonoids (curcumin, kaempferol, myricetin, quercetin, naringenin, apigenin, genistein epigallocatechin gallate), stilbenes (resveratrol), carotenoids (crocin, lycopene, lutein), and anthraquinone (Emodin). However, low chemical stability, poor water solubility, and short systemic half-life impede their clinical utility. The implication of nano-technological approaches to decode the pharmacokinetic challenges associated with phytochemical usage, as well as selective drug targeting, have markedly enhanced the pre-clinical anti-cancer activity, thus aiding in their clinical translation. This review documented the recent advances in utilizing phytochemicals for breast cancer prevention and lipidbased nanotechnological approaches for circumventing their pharmacokinetic concerns to enhance their systemic availability, cytotoxicity, and targeted delivery against breast cancer alone as well as in combination with conventional therapeutic agents.

The phytochemical plumbagin: mechanism behind its "pleiotropic" nature and potential as an anticancer treatment.

Chemotherapeutics are most often used to treat cancer, but side effects, drug resistance, and toxicity often compromise their effectiveness. In contrast, phytocompound plumbagin possesses a distinct pleiotropic nature, targeting multiple signaling pathways, such as ROS generation, cell death, cellular proliferation, metastasis, and drug resistance, and is shown to enhance the efficacy of chemotherapeutic drugs. Plumbagin has been shown to act synergistically with various chemotherapeutic drugs and enhance their efficacy in drug-resistant cancers. The pleiotropic nature is believed to be due to plumbagin's unique structure, which contains a naphthoquinone ring and a hydroxyl group responsible for plumbagin's various biological responses. Despite limitations such as restricted bioavailability and delivery, recent developments aim to address these challenges and harness the potential of plumbagin as an anticancer therapeutics. This review delves into the structural aspect of the plumbagin molecule contributing to its pleiotropic nature, explores the diverse mechanism that it targets, and discusses emerging strategies to overcome its limitations.

Toralactone alleviates cisplatin-induced acute kidney injury by modulating the gut microbiota-renal axis

BackgroundGut microbiota has been reported to be perturbed by cisplatin and to modulate the nephrotoxicity of chemotherapeutic agents. However, the critical role of toralactone, a bioactive components of Cassia obtusifolia L. seeds, in modulating the gut microbiota in the pathogenesis of cisplatin-induced nephrotoxicity remains to be elucidated. Methods: In this study, we verified the reno-protective effects of toralactone and compared the composition and function of the gut microbiota in the normal, cisplatin-treated and low or high dose of toralactone-treated mice using 16S rDNA gene sequencing. We also investigated the gut microbiota related LPS/TLR4/NF-κB/TNF-α pathway in renal tissue. To elucidate the causal relationship between gut dysbiosis and cisplatin nephrotoxicity, an antibiotic cocktail was administered to deplete the gut microbiota and fecal microbiota transplantation (FMT) was performed prior to cisplatin treatment. Results: The renal histopathology showed that toralactone significantly alleviated cisplatin-induced renal injury. 16S rDNA gene sequencing analysis demonstrated that toralactone treatment effectively reversed cisplatin-induced gut microbiota dysbiosis in mice. FMT from toralactone-treated mice to cisplatin-induced kidney injury mice was observed to have the reno-protective effects, and deletion of gut microbiota by antibiotics was found to negate the reno-protective effect of toralactone. Interestingly, the renal tissue of cisplatin-associated kidney injury mice showed activation of the LPS/TLR4/NF-κB pathway and increase in TNF-α within the renal tissue, whereas toralactone treatment was observed to inhibit the LPS/TLR4/NF-κB/TNF-α pathway. Conclusion: This study elucidated the reno-protective effects for the first time, demonstrating that it exerts its beneficial effects through the gut microbiota, which mediate the LPS/TLR4/NF-κB/TNF-α inflammatory pathway. It may help to develop therapeutic approaches using toralactone and targeted restoration of the gut microbiota.

A Ru(II) Polypyridyl Complex Bearing Bathocuproine Ligand is a Potent Chemotherapeutic Agent Against Chemically Induced Skin Cancer Model

A Ru(II) Polypyridyl Complex Bearing Bathocuproine Ligand is a Potent Chemotherapeutic Agent Against Chemically Induced Skin Cancer Model

Recent advances in anticancer mechanisms of molecular glue degraders: focus on RBM39-dgrading synthetic sulfonamide such as indisulam, E7820, tasisulam, and chloroquinoxaline sulfonamide.

Synthetic sulfonamide anticancer drugs, including E7820, indisulam, tasisulam, and chloroquinoxaline sulfonamide, exhibit diverse mechanisms of action and therapeutic potential, functioning as molecular glue degraders. E7820 targets RBM39, affecting RNA splicing and angiogenesis by suppressing integrin α2. Phase I studies have demonstrated some stability in advanced solid malignancies; however, further efficacy studies are required. Indisulam causes G1 cell cycle arrest and delays the G1/S transition by modulating splicing through RBM39 degradation via DCAF15. Despite its limited initial efficacy, it shows promise in combination therapies, particularly for hematopoietic malignancies and gliomas. Tasisulam inhibits VEGF signaling, suppresses angiogenesis, and induces apoptosis. Although early trials indicated broad activity, safety concerns have halted its development. Chloroquinoxaline sulfonamide, initially investigated for cell cycle arrest and topoisomerase II inhibition, was discontinued owing to its limited efficacy and toxicity, despite promising initial results. Recent studies revealed the structural interaction of E7820 with DCAF15 and RBM39, although phase II trials on myeloid malignancies have shown limited efficacy. Indisulam is effective against glioblastoma and neuroblastoma, with potential synergy in combination therapies and metabolic disruption. Recent research on tasisulam reveals its potential in cancer therapy by targeting RBM39 degradation through DCAF15-mediated pathways. Understanding these mechanisms could lead to new treatments that affect alternative splicing and improve cancer therapies Overall, although these drugs exhibit promising mechanisms of action, further research is required to optimize their clinical efficacy and safety.

Essential Oil Extracted from Lippia sidoides Cham. (Verbenaceae) Induces Cell Cycle Arrest, Apoptosis, and Antimigratory Effects in Melanoma Cells.

Melanoma, the most aggressive form of skin cancer, poses a substantial global health threat with increasing incidence rates. Although novel targeted therapies have improved melanoma treatment, challenges persist due to poor response rates and drug resistance. Plant-derived compounds have been crucial in anticancer drug discovery, with many natural products demonstrating the ability to target molecular pathways involved in tumor development. In this study, the anti-melanoma potential of essential oil extracted from the aerial parts of Lippia sidoides Cham. (EO-LS), composed mainly by the monoterpene thymol (96%), was demonstrated. Obtained results demonstrated that EO-LS disrupted critical cancer hallmarks in A2058 melanoma cells harboring the BRAFV600E mutation. Specifically, EO-LS induced G1-phase cell cycle arrest and apoptosis, as assessed by annexin-V, caspase-3 activity, and TUNEL assays. EO-LS also inhibited cell migration and disrupted the AKT signaling pathway, which is a critical regulator of melanoma progression. Furthermore, a dose-dependent increase in reactive oxygen species (ROS) generation was observed, indicating pro-oxidant properties. These findings highlighted the significant in vitro anticancer properties of EO-LS suggesting its potential as a promising molecular scaffold for developing of novel anti-melanoma candidates.

Pharmacovigilance study of the association between peripheral neuropathy and antibody–drug conjugates using the FDA adverse event reporting system

Antibody–drug conjugates (ADCs) are among the fastest-growing classes of anticancer drugs, making it crucial to evaluate their potential for causing peripheral neuropathy. We analyzed data from the FAERS database (January 1, 2014, to June 30, 2023) using disproportionality and Bayesian methods. We identified 3076 cases of ADC-associated peripheral neuropathy. Our study revealed significant signals for all ADCs (ROR 1.82, 95% CI 1.76–1.89). ADCs with tubulin-binding payloads showed significant peripheral neuropathy signals (ROR 2.31, 95% CI 2.23–2.40), whereas those with DNA-targeting (ROR 0.48, 95% CI 0.39–0.59) and topoisomerase 1 inhibitor (ROR 0.56, 95% CI 0.48–0.66) payloads exhibited non-significant signals. Signals for peripheral sensory neuropathy were 4.83, 2.44, 2.74, and 2.21 (calculated based on IC025) for brentuximab vedotin, trastuzumab emtansine, enfortumab vedotin, and polatuzumab vedotin, while signals for peripheral motor neuropathy were 5.31, 0.34, 2.27, and 0.03, respectively. The median time to onset for all ADCs was 127 days (interquartile range 40–457). Tisotumab vedotin had the highest hospitalization rate at 26.67%, followed by brentuximab vedotin at 25.5%. Trastuzumab emtansine had the highest mortality rate ,with 80 deaths (11.96%) among 669 cases. Based on FAERS database, only ADCs with tubulin-binding payloads exhibited significant peripheral neuropathy signals. Brentuximab vedotin and enfortumab vedotin showed similar profiles for peripheral sensory neuropathy and motor neuropathy. Given the delayed time to onset and potentially poor outcomes, ADC-related peripheral neuropathy warrants significant attention.

Expanding on the plecstatin anticancer agent class: exchange of the chlorido ligand for N-heterocyclic ligands

Expanding on the plecstatin anticancer agent class: exchange of the chlorido ligand for N-heterocyclic ligands

Engineered PLGA Core-Lipid Shell Hybrid Nanocarriers Improve the Efficacy and Safety of Irinotecan to Combat Colon Cancer.

Poly(lactide-co-glycolide) (PLGA) is a biocompatible and biodegradable copolymer that has gained high acceptance in biomedical applications. In the present study, PLGA (Mw = 13,900) was synthesized by ring-opening polymerization in the presence of a biocompatible zinc-proline initiator through a green route. Irinotecan (Ir) loaded with efficient PLGA core-lipid shell hybrid nanocarriers (lipomers, LPs) were formulated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000] (DSPE-PEG-2000), using soya lecithin, by a nanoprecipitation method, and the fabricated LPs were designated as P-DSPE-Ir and P-DSPE-PEG-Ir, respectively. The formulated LPs were further validated for their physicochemical properties and biological potential for colon cancer application. The potential delivery of a poorly water-soluble chemotherapeutic drug (Ir) was studied for the treatment of colon cancer. LPs were successfully prepared, providing controlled size (80-120 nm) and surface charge (∼ -35 mV), and the sustained release properties and cytotoxicity against CT-26 colon cancer cells were studied. The in vivo biodistribution and tumor site retention in CT-26 xenograft tumor-bearing Balb/C mice showed promising results for tumor uptake and retention for a prolonged time period. Unlike P-DSPE-Ir, the P-DSPE-PEG-Ir LP exhibited significant tumor growth delay as compared to untreated and blank formulation-treated groups in CT-26 (subcutaneous tumor model) after 4 treatments of 10 mg irinotecan/kg dose. The biocompatibility and safety of the LPs were confirmed by an acute toxicity study of the optimized formulation. Overall, this proof-of-concept study demonstrates that the PLGA-based LPs improve the efficacy and bioavailability and decrease neutropenia of Ir to combat colon cancer.

Carrier-Free Nanoagent Interfering with Cancer-Associated Fibroblasts' Metabolism to Promote Tumor Penetration for Boosted Chemotherapy.

Elevated production of extracellular matrix (ECM) in tumor stroma is a critical obstacle for drug penetration. Here we demonstrate that ATP-citrate lyase (ACLY) is significantly upregulated in cancer-associated fibroblasts (CAFs) to produce tumor ECM. Using a self-assembling nanoparticle-design approach, a carrier-free nanoagent (CFNA) is fabricated by simply assembling NDI-091143, a specific ACLY inhibitor, and doxorubicin (DOX) or paclitaxel (PTX), the first-line chemotherapeutic drug, via multiple noncovalent interactions. After arriving at the CAFs-rich tumor site, NDI-091143-mediated ACLY inhibition in CAFs can block the de novo synthesis of fatty acid, thereby dampening the fatty acid-involved energy metabolic process. As the lack of enough energy, the energetic CAFs will be in a dispirited state that is unable to produce abundant ECM, thereby significantly improving drug perfusion in tumors and enhancing the efficacy of chemotherapy. Such a simple drug assembling strategy aimed at CAFs' ACLY-mediated metabolism pathway presents the feasibility of stromal matrix reduction to potentiate chemotherapy.

Implementation and Evaluation of APOTECAchemo in a Community Cancer Center: A Comparative Study of Robotic Versus Manual Antineoplastic Preparation

Background: The ever-increasing complexity and demand for antineoplastic therapy necessitates innovative solutions to improve the accuracy and safety of drug preparation. Objective: To evaluate the utilization of an advanced robotic chemotherapy drug compounding system (APOTECAchemo) at a Community Cancer Center (CCC), examining accuracy, efficiency, and staff perceptions. Methods: This single-center, retrospective study evaluated the preparation of 7 intravenous (IV) antineoplastics at a CCC over a 1-year period. We compared manual methods with the APOTECAchemo system. The primary measure of accuracy was the absolute drug error percentage, with a comparison of pass and fail rates. Secondary endpoints included the overall use of APOTECAchemo for all IV antineoplastic preparations and average preparation times. An end-user satisfaction survey gathered feedback from pharmacists and pharmacy technicians. Results: A total of 8210 doses were prepared at the CCC, with 52.1% compounded by APOTECAchemo and 47.9% manually. Of these, the CCC prepared 5526 doses of the 7 routinely compounded antineoplastics. APOTECAchemo prepared 3851 (69.7%) doses, while manual compounding accounted for 1675 (30.3%) doses. The average absolute drug error was 1.44% (95% CI, 1.35-1.53) with robot compounding versus 1.17% (95% CI, 1.03-1.32) with manual ( P < 0.001). The overall failure rate was 0.72%. There were 25 failed doses (0.45%), with 8 (0.2%) failures attributed to APOTECAchemo and 17 (1%) to manual compounding ( P < 0.001). The average dose preparation time was longer with APOTECAchemo compared with manual methods. The end-user satisfaction survey indicated a positive reception toward APOTECAchemo. Conclusions: Our study demonstrates the successful implementation, extensive utilization, and high accuracy of both APOTECAchemo and manual compounding methods in the preparation of routinely administered antineoplastics at a CCC.

Synthesis and Structure of 5-Methyl-9-(trifluoromethyl)-12H-quino[3,4-b][1,4]benzothiazinium Chloride as Anticancer Agent

Synthesis and Structure of 5-Methyl-9-(trifluoromethyl)-12H-quino[3,4-b][1,4]benzothiazinium Chloride as Anticancer Agent