New Class Of Chemotherapeutic Agents Research Articles

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021-Present).

Cancer is a complicated, multifaceted disease that can impact any organ in the body. Various chemotherapeutic agents have a low selectivity and are very toxic when used alone or in combination with others. Resistance is one of the most important hurdles that develop due to the use of many anticancer therapeutics. As a result, treating cancer requires a target-specific palliative care strategy. Remarkable scientific discoveries have shed light on several of the molecular mechanisms underlying cancer, resulting in the development of various targeted anticancer agents. One of the most important heterocyclic motifs is quinazoline, which has a wide range of biological uses and chemical reactivities. Newer, more sophisticated medications with quinazoline structures have been found in the last few years, and great strides have been made in creating effective protocols for building these pharmacologically active scaffolds. A new class of chemotherapeutic agents known as quinazoline-based derivatives possessing anticancer properties consists of several well-known compounds that block different protein kinases and other molecular targets. This review highlights recent updates (2021-2024) on various quinazoline-based derivatives acting against different protein kinases as anticancer chemotherapeutics. It also provides guidance for the design and synthesis of novel quinazoline analogues that could serve as lead compounds.

Small molecule inhibitors of human RGS2 developed by structure based drug design approach

Regulators of G‐protein signaling (RGS) is a family of approximately 30 proteins that bind to the alpha subunits of G‐proteins (Galpha) and accelerate their GTP hydrolysis rates. This deactivates the G‐protein and terminates G‐Protein Coupled Receptors (GPCRs) signaling. RGS proteins, therefore, play important roles in regulating GPCR signaling and most members are implicated in human diseases such as hypertension, depression, and others. Regulator of G‐protein Signaling 2 (RGS2) is a regulator of angiotensin‐II receptor signaling and a modulator of oxytocin receptor signaling as well. More importantly, RGS2 was reported to be over expressed in the majority of solid breast cancers and in metastatic prostate cancer. For this reason, we sought to develop RGS2 inhibitors as potential chemotherapeutic agents. We utilized structure‐based drug design approaches to develop inhibitors of RGS2‐Galpha‐q interactions. Available structures of the RGS2‐Galpha complex were used to extract a pharmacophore model for searching of commercially available chemical databases. The identified hits were docked to different RGS structures to screen for compounds with the highest binding potential and most selectivity towards RGS2. We report the first group of inhibitors of RGS2‐Galpha‐q interactions developed through rational drug design that interfered with RGS2 signaling in cell‐based assays. In addition, inhibitor AJ‐3 inhibited the growth of MCF‐7 breast cancer cells in cell culture assays, which suggests that RGS2 inhibitors may have a potential to be a new class of chemotherapeutic agents.

Therapeutic progression of quinazolines as targeted chemotherapeutic agents.

Presently cancer is a grave health issue with predominance beyond restrictions. It can affect any organ of the body. Most of the available chemotherapeutic drugs are highly toxic, not much selective and eventually lead to the development of resistance. Therefore, a target specific palliative approach for the treatment of cancer is required. Remarkable advancements in science have illuminated various molecular pathways responsible for cancer. This has resulted in abundant opportunities to develop targeted anticancer agents. Quinazoline nucleus is a privileged scaffold with significant diversified pharmacological activities. Numerous established anticancer quinazoline derivatives constitute a new class of chemotherapeutic agents which are found to act by inhibiting various protein kinases as well as other molecular targets. A recent update on various quinazoline derivatives acting on different types of molecular targets for the treatment of cancer has been compiled in this review. Brief SAR studies of quinazoline derivatives acting through different mechanisms of action have been highlighted. The comprehensive medicinal chemistry aspects of these agents in this review provide a panoramic view to the biologists as well as medicinal chemists working in this area and would assist them in their efforts to design and synthesize novel quinazoline based anticancer compounds.

The synergistic proapoptotic effect of PARP-1 and HDAC inhibition in cutaneous T-cell lymphoma is mediated via Blimp-1

AbstractThe therapy of advanced mycosis fungoides (MF) presents a therapeutic challenge, and the search for new therapeutic targets is ongoing. Poly(ADP-ribose) polymerase 1 was shown to be upregulated in patients with advanced MF and could be druggable by a new class of chemotherapeutic agents, PARP-1 inhibitors, which are already in clinical trials for other malignancies; however, the role of PARP-1 inhibitors in MF has never been established. We examined the efficacy of talazoparib in the murine model of cutaneous T-cell lymphoma. The cytotoxic effect of talazoparib on Moloney MuLV-induced T-cell lymphoma (MBL2) cells was a result of G2/M cell cycle arrest via the upregulation of p53. The in vivo experiments confirmed the clinical impact of talazoparib on MF tumors. When talazoparib was combined with the histone deacetylase (HDAC) inhibitor, romidepsin, the cytotoxic effect was synergized via downregulation of the DNA-repair genes Fanconianemia complementation group A (FANCA), Fanconi anemia complementation group D2 (FANCD2), and DNA topoisomerase II binding protein 1(TOPBP1)and stimulation of apoptosis via Blimp-1 (PRDM1)/Bax axis. Romidepsin increased the expression of IRF8and Bcl-6, leading to upregulation of Blimp1and Bax; whereas talazoparib upregulated Blimp-1 and Bax via upregulation of interferon regulatory factor 4 (IRF4), leading to cleavage of caspases 6 and 7. Thus, a combination of talazoparib with romidepsin demonstrated the synergistic antilymphoma effect and warranted further investigation in a clinical trial.

Nano-sponges: A Novel Carrier for Delivery of Chemo-therapeutic Drugs

Nano-sponges belong to the category of hyper-cross linked polymer which is based on the colloidal structure. Nano-sized carriers are developed recently and are being used to deliver poorly water soluble drug by modifying the pharmaco-kinetic parameter and provide enhanced prolonged release. As a new class of chemo-therapeutic agents is being developed, formulation is getting difficult to issues such as poor solubility, low loading capacity and less entrapment of the drug in the drug delivery system. Nano-sponges have shown to deliver the most complex and challenging Chemo therapeutic drugs due to its amphiphilic nature. Nano-sponges tend to adhere to the tumor through complex bonding and release the drugs at the tumor site,in response to the stimuli such as temperature and pH thus providing the much needed targeted drug delivery. Nano-sponge delivery system has been able to resolve the bio-availability, dose regime, enhanced formulation flexibility issues and fewer side effects while delivering the chemo-therapeutic drugs. Nano-sponges are usually prepared by cross-linking suitable polymer such as Beta-cyclodextrin with cross-linkers. The below comprehensive articles is a brief review of all chemo-therapeutic agent formulated in the Nano-sponge and various methods for the synthesis of Nano-sponges and loading of the active components in the Nano-sponge drug delivery system.

Synthesis and biological evaluation of novel 2-imino-4-thiazolidinone derivatives as potent anti-cancer agents

A new series of 2-imino-4-thiazolidinone derivatives (7a–7t) has been synthesised and screened for their cytotoxicity against three cancer cell lines (B16F10, A549, PANC-1) and normal cell line (CHO). Among the compounds tested, compounds 7k, 7m, 7n showed potent cytotoxicity against B16F10 cell line with IC50 between 3.4 and 7μM. Interestingly these three compounds are non toxic to non cancerous CHO cells and induced apoptosis in B16F10 cells observed by DNA damage analysis through PI/Hoechst double staining method. Compounds 7k and 7n induced G0/G1 cell cycle arrest while compound 7m induced G2/M cell cycle arrest in B16F10 cells which confirms that these compounds have role in cancer cell cycle regulation. Additionally, compound 7m showed generation of intracellular reactive oxygen species (ROS) in B16F10 cells that may contribute in the cell cycle arrest whereas compounds 7k and 7n show anti-cancer activity through independent of ROS formation. Induction of apoptosis, cell cycle arrest in B16F10 cells are found to be the anti-cancer mechanism of these three compounds. The results all together demonstrate the potent cytotoxic nature of these compounds in cancer cells could be considered as new class of chemotherapeutic agents in near future.

Abstract 1231: Novel chromene analogs as small-molecule microtubule destabilizers for the treatment of chemo-resistant ovarian cancer

Abstract Ovarian cancer is the most lethal gynecological malignancy with a 5-year survival rate of less than 40%, primarily because of treatment failure due to emergence of chemo-resistance to standard agents. This indicates a dire need for new treatments to improve survival rates. The tubulin dynamics is a promising target for new chemotherapeutic agents. In continuation of our efforts, using medicinal chemistry approach, we recently identified small molecular inhibitors of tubulin polymerization called chromenes, as new ovarian anti-cancer agents. A set of chromene compounds were screened for anti-cancer effect on cisplatin sensitive (A2780, SKOV-3, TOV112D) and cisplatin resistant (OVCAR-3, A2780-cisR, TOV112D-cisR) ovarian cancer cells. In vitro cell viability was assessed by fluorescence based Alamar Blue assay. Our preliminary studies identified SP-6-27 (IC50 range: 0.102± 0.006 - 2.24±0.056 μM) and SP-6-37 (IC50 range: 0.258± 0.159 - 3.61±0.049 μM) as most potent chromene analogs. Both compounds exhibited a potent anticancer activity towards both cisplatin sensitive (SP-6-27 IC50: 0.14± 0.03 μM; SP-6-37 IC50: 1.35± 0.88 μM) and cisplatin resistant (SP-6-27 IC50: 0.81± 1.2 μM; SP-6-37 IC50: 2.09± 1.7 μM) cell lines. The compounds exhibited least cytotoxicity towards normal ovarian epithelial cells (SP-6-27- IC50: 83.35 ± 9.47 μM; SP-6-37- IC50: 75.77 ± 5.37 μM). Additionally, the analysis of apoptotic changes as determined by Annexin-V assay revealed an enhanced apoptosis in both cisplatin sensitive and resistant cells upon treatment with compounds SP-6-27 or SP-6-37. Together, the data demonstrates that ovarian cancer cell lines respond sensitively to SP-6-27 and SP-6-37, demonstrating that the chromene scaffold is effective in suppressing ovarian cancer cell growth. The findings indicate that the novel chromene analogs are a new class of chemotherapeutic agents that will offer advantages for the treatment of ovarian cancer. Citation Format: Arpita Kulshrestha, Safaa A. Ibrahim, Gajendra K. Katara, Renukadevi Patil, Shivaputra Patil, Kenneth D. Beaman. Novel chromene analogs as small-molecule microtubule destabilizers for the treatment of chemo-resistant ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1231.

PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting.

Poly(ADP-ribose) polymerases have shown true promise in early clinical studies due to reported activity in BRCA-associated cancers. PARP inhibitors may represent a potentially important new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. In addition, a more sophisticated understanding of the toxicity profile is required if PARP inhibitors are to be employed in the curative, rather than the palliative, setting. PARP inhibitors have successfully moved into clinical practice in the past few years, with approval granted from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past two years. The United States FDA approval of olaparib applies to fourth-line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval of olaparib for maintenance therapy in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. This review covers the current understanding of PARP, its inhibition, and the basis of the excitement surrounding these new agents. It also evaluates future approaches and directions required to achieve full understanding of the intricate interplay of these agents at the cellular level.

KLF4-SQSTM1/p62-associated prosurvival autophagy contributes to carfilzomib resistance in multiple myeloma models.

Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. Because of a high rate of immunoglobulin synthesis, the endoplasmic reticulum of MM cells is subjected to elevated basal levels of stress. Consequently, proteasome inhibitors, which exacerbate this stress by inhibiting ubiquitin-proteasome-mediated protein degradation, are an important new class of chemotherapeutic agents being used to combat this disease. However, MM cells still develop resistance to proteasome inhibitors such as carfilzomib. Toward this end, we have established carfilzomib-resistant derivatives of MM cell lines. We found that resistance to carfilzomib was associated with elevated levels of prosurvival autophagy, and Kruppel-like factor 4 (KLF4) was identified as a contributing factor. Expression levels as well as nuclear localization of KLF4 protein were elevated in MM cells with acquired carfilzomib resistance. Chromatin immunoprecipitations indicated that endogenous KLF4 bound to the promoter regions of the SQSTM1 gene encoding the ubiquitin-binding adaptor protein sequestosome/p62 that links the proteasomal and autophagic protein degradation pathways. Ectopic expression of KLF4 induced upregulation of SQSTM1. On the other hand, inhibitors of autophagy sensitized MM cells to carfilzomib, even in carfilzomib-resistant derivatives having increased expression of the multidrug resistance protein P-glycoprotein. Thus, we report here a novel function for KLF4, one of the Yamanaka reprogramming factors, as being a contributor to autophagy gene expression which moderates preclinical proteasome inhibitor efficacy in MM.

Capridine-β, a new class of chemotherapeutic agents for prostate cancer.

e16062 Background: Available targeted chemotherapy for prostate cancers (CaP) is limited. We are developing a nitroacridine (NA) derivative, 9-hydroxy-ethylamino-4-methyl-1 nitroacridine, C-1748 (C...

Mitochondria-targeted Resveratrol Derivatives Act as Cytotoxic Pro-oxidants

Resveratrol derivatives bearing an O-linked mitochondria-targeting 4-triphenylphosphoniumbutyl group at either position 3 or position 4' are prooxidant and cytotoxic for cultured cells, selectively killing fast-growing cells when supplied in the low μM range. Resveratrol is essentially without effect under these experimental conditions, while the cytotoxicity of the mitochondriotropic derivatives increases if they are methylated on the remaining hydroxyls. Experiments with Bax(-/-)/Bak(-/-) cells and a pan-caspase inhibitor show that cell death is mostly of the necrotic type. Cytotoxicity is due to ROS produced upon accumulation of the compounds into mitochondria, and specifically to H2O2, since externally added membrane-permeant catalase largely prevents cell death while superoxide dismutase potentiates toxicity. The mitochondriotropic compounds cause ROS-independent depolarization of in situ mitochondria. Effectiveness is increased if resveratrol hydroxyls are acetylated or methylated; this excludes the involvement of autooxidation of the polyphenolic nucleus and a protonophoric cycle as the causes of ROS generation and of depolarization, respectively. Resveratrol-triphenylphosphonium conjugates may thus represent a new class of chemotherapeutic agents, redox-active "mitocans", whose mechanisms of action and in vivo activity are worthy of further investigation.

The Clinical Spectrum of Bortezomib-Induced Peripheral Neuropathy (P06.140)

Objective: We sought to investigate the incidence, risk factors for development and phenotype of peripheral neuropathy in patient9s treated with bortezomib. Background Bortezomib (Velcade®) is the first member of a new class of chemotherapeutic agents that inhibit the proteasome-ubiquitination pathway. It is FDA-approved for use in multiple myeloma and mantle cell lymphoma. Bortezomib causes a painful axonal sensory-predominant length-dependent peripheral neuropathy in 30-40% of patients. A small subgroup of patients treated with bortezomib develop a severe neuropathy soon after commencing bortezomib, the mechanism of which is unclear. Design/Methods: We searched the Mayo Clinic Hematology Chemotherapy database for patients treated with bortezomib. We reviewed the clinical information to determine if neuropathy occurred in relation to the initiation of bortezomib. We reviewed the clinical and electrophysiological features and long-term followup of patients evaluated by a neurologist. Subjects were included if they received bortezomib and had follow-up for at least one cycle of chemotherapy. Results: 589 patients were identified. 378 patients met inclusion criteria. 138 (36.5%) were determined to have treatment-emergent peripheral neuropathy. The typical pattern was a painful, sensory-predominant peripheral neuropathy involving the hands and feet. Three patients had evidence of a plexopathy or polyradiculoneuropathy. Two patients had nerve biopsies suggesting microvasculitis. A prior history of peripheral neuropathy was more common in patients with treatment-emergent peripheral neuropathy (22% vs 14%, p Conclusions: In our series the incidence of bortezomib-induced peripheral neuropathy is 36.5%, similar to previous reports. A prior history of peripheral neuropathy appears to be a risk factor for the development of bortezomib-induced peripheral neuropathy. The pattern is most commonly a painful, sensory-predominant length-dependent neuropathy. An inflammatory neuropathy or polyradiculoneuropathy can occur with bortezomib with biopsy features suggesting microvasculitis. Disclosure: Dr. Mauermann has nothing to disclose. Dr. Dispenzieri has received research support from Millennium. Dr. Staff has nothing to disclose.

Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells

Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer.

Abstract A32: Novel ceramide analogs induce apoptosis in chemoresistant breast cancer.

Abstract Ceramide, a central molecule in sphingolipid metabolism, has been shown to mediate cell death by both apoptotic and non-apoptotic pathways. However, the use of endogenous ceramides as a pharmacological intervention is limited by the naturally hydrophobic nature of the ceramide molecule, which prevents efficient penetration of the cellular membrane. One novel approach is to synthesize ceramide analogs with a greater efficacy and specificity than endogenous ceramides. Our laboratory has previously shown that ceramide analogs have therapeutic potential in the treatment of chemo-sensitive and -resistant breast cancer. In this study, the effect of 5 novel ceramide analogs (designated 401–406) on cellular viability and clonogenic survival was examined in the chemosensitive MCF-7, endocrine-resistant MDA-MB-231, and chemoresistant MCF-7TN-R breast cancer cell lines, as well as the Human Embryonic Kidney (HEK) cell line. In the viability assay, analogs 401 and 406 showed the greatest efficacy in the MCF7-TNR cell line, with IC50 values of 4.0 μM and 4.2 μM in metastatic MCF-7TN-R cells. In the clonogenic survival assay, analogs 401 and 406 were again the most effective in the MCF7-TNR cell line with IC50 values of 1.9 and 1.8 respectively. Additionally, Analog 406 showed a 3.8 fold increase over control in the induction of apoptosis (p<0.05), and demonstrated a 3.4-fold increase in caspase-9 activity (p<0.05). Because ceramide has been shown to be involved in tumor sensitivity to apoptosis and chemoresistance, we suggest that development of ceramide analogs with increased antitumor activity represents a potential new class of chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A32.

An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

Here we describe the inhibitory activity of IQG607, pentacyano(isoniazid)ferrate(II), on isoniazid-sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis, its oral toxicity, and efforts to adapt IQG607 synthesis to large chemical reactors. IQG607 represents a promising chemotherapeutic agent aiming at the inhibition of a validated and druggable molecular target.

Suberoylanilide hydroxamic acid sensitizes human oral cancer cells to TRAIL-induced apoptosis through increase DR5 expression

Suberoylanilide hydroxamic acid has been shown to selectively induce tumor apoptosis in cell cultures and animal models in several types of cancers and is about as a promising new class of chemotherapeutic agents. In addition, suberoylanilide hydroxamic acid showed synergistic anticancer activity with radiation, cisplatin, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in some cancers. Here, we report suberoylanilide hydroxamic acid also induced apoptosis in human oral cancer cells. Western blotting showed suberoylanilide hydroxamic acid increased Fas, Fas ligand, DR4, and DR5 protein expression and activated caspase-8 and caspase-9. The apoptosis was almost completely inhibited by caspase-8 inhibitor Z-IETD-FMK and attenuated by caspase-9 inhibitor Z-LEHD-FMK. Human recombinant DR5/Fc chimera protein but not Fas/Fc or DR4/Fc significantly inhibited apoptosis induced by suberoylanilide hydroxamic acid. These results suggest that suberoylanilide hydroxamic acid induces apoptosis mainly through activation of DR5/TRAIL death pathway. Furthermore, subtoxic concentrations of suberoylanilide hydroxamic acid sensitize two TRAIL resistant human oral cancer cells, SAS and Ca9-22, to exogenous recombinant TRAIL-induced apoptosis in a p53-independent manner. Combined treatment of suberoylanilide hydroxamic acid and TRAIL may be used as a new promising therapy for oral cancer.

Temozolomide with radiation therapy in high grade brain gliomas: pharmaceuticals considerations and efficacy; a review article.

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) which have a combined incidence of 5–8/100,000 population, represent the most common primary central nervous system tumors. The treatment outcomes even with aggressive approach including surgery, radiaton therapy and chemotherapy are dismal with median reported survival is less than 1 year. Temozolomide is a new drug which has shown promise in treating malignant gliomas and other difficult-to-treat tumors. This drug is a per os (p.o) imidazotetrazine second-generation alkylating agent which represents the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. The efficacy of temozolomide was tested in vitro studies and has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma (HGG). In addition, in clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Moreover, preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. At the present time temozolomide is approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Temozolomide’s characteristics which make it a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types are its predictable bioavailability and minimal toxicity. An overview of the mechanism of action of temozolomide and a summary of results from more important randomized controlled clinical trials in high grade gliomas are presented here.

Tubulin: A Target for Antineoplastic Drugs into the Cancer Cells but also in the Peripheral Nervous System

Since the introduction into clinical practice of vinca alkaloids, tubulin has become a key and well-established target of modern antineoplastic chemotherapy. When taxanes became available their broad spectrum of activity was striking and opened up new horizons for cancer patients' treatment. However, taxanes' susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein, is not infrequent and their use may be limited by poor solubility, synthetic problems and toxicity. The epothilones are a new class of chemotherapeutic agents with a mechanism of action similar to that of taxanes, but different enough to escape, for example, the multidrug resistance caused by P-glycoprotein. Moreover, the epothilones (that are strong promoters of tubulin polymerization) have significant antitumor activity against human cancer cells that are taxane-resistant, express the multidrug resistance gene MDR-1, and have acquired tubulin mutations. Finally, starting from the natural molecules, several synthetic analogues have been developed. Besides their antineoplastic efficacy, all the antitubulin drugs share a common toxicity on the peripheral nervous system and peripheral neurotoxicity is a major, potentially dose-limiting side effect also of the epothilones. The current knowledge regarding the features of epothilones' peripheral neurotoxicity and their comparison with taxanes will be reviewed.

Nimesulide inhibits IFN-γ-induced programmed death-1-ligand 1 surface expression in breast cancer cells by COX-2 and PGE 2 independent mechanisms

It is now well established that increased programmed death-1-ligand 1 (PD-L1) surface expression in cancer cells and the resultant T cell suppression contribute to cancer cell immune evasion. Blockade of PD-L1 function has been shown to stimulate anti-cancer immunity. Therefore, compounds that can down-regulate PD-L1 surface expression in cancer cells may serve as novel immune modulators to promote cancer cell-reactive immune responses. In the present study, we examined the effects of nimesulide, a selective COX-2 inhibitor, on PD-L1 surface expression in breast cancer cells by flow cytometry. We demonstrated that nimesulide was able to inhibit IFN-γ-induced PD-L1 surface expression in breast cancer cells. However, our data indicate that the inhibitory effects of nimesulide appear to be independent of COX-2/PGE 2 signaling. Since nimesulide also exhibits anti-tumor activities by inducing cancer cell apoptosis and inhibiting cancer cell proliferation, our findings suggest that nimesulide may represent a new class of chemotherapeutic agents that possess dual functions to inhibit cancer cell growth and promote cancer cell immune responses.

Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways

Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic agents. Our laboratory has recently reported that phenylhexyl isothiocyanate (PHI), a synthetic isothiocyanate, is an inhibitor of HDAC. In this study we examined whether PHI is a hypomethylating agent and its effects on myeloma cells. RPMI8226, a myeloma cell line, was treated with PHI. PHI inhibited the proliferation of the myeloma cells and induced apoptosis in a concentration as low as 0.5 μM. Cell proliferation was reduced to 50% of control with PHI concentration of 0.5 μM. Cell cycle analysis revealed that PHI caused G1-phase arrest of RPMI8226 cells. PHI induced p16 hypomethylation in a concentration- dependent manner. PHI was further shown to induce histone H3 hyperacetylation in a concentration-dependent manner. It was also demonstrated that PHI inhibited IL-6 receptor expression and VEGF production in the RPMI8226 cells, and reactivated p21 expression. It was found that PHI induced apoptosis through disruption of mitochondrial membrane potential. For the first time we show that PHI can induce both p16 hypomethylation and histone H3 hyperacetylation. We conclude that PHI has dual epigenetic effects on p16 hypomethylation and histone hyperacetylation in myeloma cells and targets several critical processes of myeloma proliferation.