Efficacy Of Chemotherapy In Cancer Research Articles

β-Glucuronidase-Responsive Albumin-Binding Prodrug of Colchicine-Site Binders for Selective Cancer Therapy.

The development of novel therapeutic strategies enabling the selective destruction of tumors while sparing healthy tissues is of great interest to improve the efficacy of cancer chemotherapy. In this context, we designed a β-glucuronidase-responsive albumin-binding prodrug programmed to release a potent Isocombretastatin A-4 analog within the tumor microenvironment. When injected at a non-toxic dose in mice bearing orthotopic triple-negative mammary tumors, this prodrug produced a significant anticancer activity, therefore offering a valuable alternative to the systemic administration of the parent drug.

The unexpected PD-L1 suppression function of celery-derived extracellular vesicles improves lung cancer chemotherapy efficacy.

Aim: The article explores celery-derived extracellular vesicles (CDEVs), characterized by high cellular uptake, low immunogenicity, and high stability, as a therapeutic strategy for antitumor nanomedicines. Methods: The methods employed in this study include in vitro cell experiments such as co-culture, Western Blot, and flow cytometry. In vivo experiments were conducted in C57BL/6 tumor-bearing mice subcutaneously injected with Lewis lung carcinoma (LLC) cells. The experiments encompassed parameters such as survival rate, body weight, tumor size, flow cytometry, immunohistochemistry, and spectral live imaging system. Results: Our study revealed that CDEVs could be used as drugs to effectively downregulate the phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/programmed cell death ligand 1 (PD-L1) axis in lung cancer cells. In co-culture experiments, CDEVs were observed to impede the expression of PD-L1, thereby interfering with the interaction between PD-L1 and programmed death 1 (PD-1) and subsequently preventing the suppression of T cells. In in vivo distribution experiments, CDEVs loaded with paclitaxel (PTX) demonstrated better tumor targeting capabilities. Remarkably, following CDEVs-PTX treatment, CD8+ T cell levels in mice were increased, presumably leading to improved antitumor effects. Conclusion: CDEVs not only serve as drug carriers but also function as drugs themselves; as such, through a single administration of CDEVs, it is possible to combine immunotherapy and chemotherapy to achieve better effects between the two, providing a more comprehensive and effective cancer treatment strategy that promises to improve treatment outcomes and reduce the adverse effects of therapy.

Abstract A027: Enhancing pancreatic cancer chemotherapy through photochemical internalisation

Abstract Introduction Pancreatic cancer is the deadliest common cancer. Its poor prognosis is associated with its complex biology and lack of early detection strategies. Although much progress has been made in finding more effective therapeutic strategies, pancreatic tumours remain difficult to treat. A major reason why chemotherapy is relatively ineffective against this type of cancer is inefficient delivery of drugs to their target sites combined with multidrug resistance. Our aim is to use the technique called Photochemical Internalisation (PCI), a light-triggered intracellular drug delivery method which combines low dose Photodynamic Therapy (PDT) with chemotherapy, to induce efficient cytosolic delivery of therapeutic compounds to their specific subcellular targets. Methodology Treatment outcomes using saporin (a type I ribosome-inactivating protein) and gemcitabine as monotherapies, or in combination with a light-activated photosensitizer (the porphyrin TPPS2a), were thoroughly analysed in both established pancreatic cancer cell lines and patient-derived xenograft (PDX) models. The efficacy of these treatments was assessed in both 2D and 3D tumour models through various cell viability assays, including MTT, crystal violet staining, and neutral red staining. Additionally, molecular techniques such as western blotting, protein arrays, and flow cytometry were employed to determine the effects on cell viability and to elucidate changes in signalling pathways leading to the therapeutic response. Results In this study, we observed minimal cytotoxicity induced by saporin, gemcitabine or TPPS2a + light monotherapies. However, PCI synergistically enhanced saporin and gemcitabine cytotoxicity (p<0.001) using very low concentrations in all tumour models. Moreover, we determined the mechanism of cell death triggered by these protocols. PCI induced endosomal disruption following light excitation and apoptosis leading to caspases 3/7 activation, in a time dependent manner. Conclusions Overall, our findings demonstrate the potential of PCI to enhance the efficacy of cancer chemotherapy for pancreatic cancer using lower doses than in monotherapy and open a new window for future translational studies. By using low doses of light therapy, we have found a promising avenue for future studies that could eventually lead to better treatments for this challenging disease. Citation Format: Maria Rosado, Ismahan Mahamed, Andres Garcia-Sampedro, Sandy MacRoberts, Pål Selbo, Stephen Pereira, Pilar Acedo. Enhancing pancreatic cancer chemotherapy through photochemical internalisation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A027.

Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as potent reversal agents against ABCB1-mediated multidrug resistance

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5μM (IC50=27.00nM, RF=247.40) and 10μM (IC50=10.07nM, RF=663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents.

Prediction of colorectal cancer chemotherapy efficacy using machine learning applied to gene expression data.

e15548 Background: FOLFOX and FOLFIRI chemotherapy are considered standard first-line treatment options for colorectal cancer (CRC). However, the criteria for selecting the appropriate treatments have not been thoroughly analyzed. Here, we aim to use machine learning and genetic profiles to identify precise multi-gene panels that can predict the response to 5-Fluorouracil-based chemotherapy in colorectal cancer patients. Methods: The genetic profiling data, including drug response profiles, were retrieved from the Gene Expression Omnibus (GEO) database. These datasets were used to train and validate machine learning models. Feature selection methods, such as least absolute shrinkage and selection operator (LASSO) and variable selection from random forests (varSelRF) and various algorithms, such as Random Forest and Support Vector Machines, were applied to develop predictive models. Functional enrichment and network analyses were performed using Ingenuity Pathway Analysis (IPA). Results: This study identified relevant gene signatures at two stages of colorectal cancer: primary and metastasis using two different chemotherapy regimens, FOLFOX and FOLFIRI. The predictive models achieved an average prediction accuracy of 93% in identifying drug response outcomes across multiple chemotherapy regimens. The application of the machine learning model suggested that 28.6% of patients who failed the treatment therapy they received would benefit from the alternative treatment. Conclusions: The developed machine learning models demonstrate potential for guiding clinicians in selecting the most effective treatment options based on individual genetic profiles. With additional clinical validation, this approach could lead to improvements in treatment outcomes for patients with CRC and other cancers.

Phosphatidylserine-targeting bis(zinc-dipicolylamine) farnesol inhibits ATP production in cancer cells to overcome multidrug resistance

Phosphatidylserine-targeting bis(zinc-dipicolylamine) farnesol inhibits ATP production in cancer cells to overcome multidrug resistance

Abstract 7192: Teriflunomide overcomes gemcitabine resistance by inhibiting the GSK3β/mTOR pathway in pancreatic cancer

Abstract Background: Pancreatic cancer (PC) is a lethal malignancy that is partly attributable to the acquisition of chemoresistance to conventional chemotherapies. Hence, developing strategies to overcome such chemoresistance is essential. Teriflunomide, an active metabolite of leflunomide, has been widely utilized in managing autoimmune disorders, and emerging evidence suggests that it can augment the efficacy of chemotherapy in cancer. We investigated the therapeutic effect of teriflunomide in overcoming resistance to Gemcitabine-based therapy in PC. Methods: We performed docking and genomewide transcriptomic profiling analyses to identify therapeutic targets of Teriflunomide associated with Gemcitabine resistance (Gem-R) in PC. Subsequently, we analyzed the TCGA dataset to determine the prognostic significance of candidate genes in PC patients. A series of experiments were performed in PC cells, and the key findings were validated in patient-derived 3D organoids and a Gem-R Mia-PaCa2 xenograft model. Results: Docking and transcriptomic profiling studies identified GSK3β, MAPK8, and MAPK9 as potential targets of Teriflunomide, which were significantly upregulated in Gem-R cell lines (P < 0.05). GSK3β was independently associated with poor overall and disease-free survival in PC patients. Combined Teriflunomide and Gemcitabine treatment exhibited superior synergistic anti-tumor potential, as evidenced by reducing PC cell proliferation, clonogenicity, invasion, and migration. The combined treatment with Teriflunomide and Gemcitabine primarily inhibited GSK3β phosphorylation, resulting in the silencing of the downstream AKT/mTOR pathway. Lentiviral-based silencing of GSK3β inhibited the AKT/mTOR pathway and reduced the IC50s of Gemcitabine in PC cells. Furthermore, co-administrating both drugs to Gem-R Mia-PaCa-2 xenograft mice significantly reduced tumor growth rates and volumes. These findings were recapitulated in patient-derived 3D-organoids, where the combined treatment resulted in fewer and smaller organoids vs. each drug individually (P < 0.05). Conclusions: We provide novel evidence that Teriflunomide helps overcome resistance to Gemcitabine by inhibiting the GSK3β/AKT/mTOR pathway, which could improve treatment outcomes in PC. Citation Format: Caiming Xu, Yuan Li, Silei Sui, Meiling Chen, Laleh Melstorm, Haiyong Han, Steven T. Rosen, Ajay Goel. Teriflunomide overcomes gemcitabine resistance by inhibiting the GSK3β/mTOR pathway in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7192.

High-accuracy prediction of colorectal cancer chemotherapy efficacy using machine learning applied to gene expression data.

Introduction: FOLFOX and FOLFIRI chemotherapy are considered standard first-line treatment options for colorectal cancer (CRC). However, the criteria for selecting the appropriate treatments have not been thoroughly analyzed. Methods: A newly developed machine learning model was applied on several gene expression data from the public repository GEO database to identify molecular signatures predictive of efficacy of 5-FU based combination chemotherapy (FOLFOX and FOLFIRI) in patients with CRC. The model was trained using 5-fold cross validation and multiple feature selection methods including LASSO and VarSelRF methods. Random Forest and support vector machine classifiers were applied to evaluate the performance of the models. Results and Discussion: For the CRC GEO dataset samples from patients who received either FOLFOX or FOLFIRI, validation and test sets were >90% correctly classified (accuracy), with specificity and sensitivity ranging between 85%-95%. In the datasets used from the GEO database, 28.6% of patients who failed the treatment therapy they received are predicted to benefit from the alternative treatment. Analysis of the gene signature suggests the mechanistic difference between colorectal cancers that respond and those that do not respond to FOLFOX and FOLFIRI. Application of this machine learning approach could lead to improvements in treatment outcomes for patients with CRC and other cancers after additional appropriate clinical validation.

Supramolecular nanoparticles based on elastin-like peptides modified capsid protein as drug delivery platform with enhanced cancer chemotherapy efficacy

Cancer, a prevalent disease posing significant threats to human health and longevity, necessitates effective therapeutic interventions. Chemotherapy has emerged as a primary strategy following surgical procedures for combating most malignancies. Despite the considerable efficacy of conventional chemotherapeutic agents against cancer cells, their utility is hindered by profound challenges such as multidrug resistance and deleterious toxic side effects, thereby limiting their systemic application. To tackle these challenges, we have devised a promising nanomedicine platform based on a plant virus. Specifically, we have selected the cowpea melanoma mottled virus (CCMV) as our nano-delivery system owing to its monodisperse and homogeneous size, as well as its intrinsic ability for controlled self-assembly. Leveraging the potential of this platform, we have engineered CCMV-based nanoparticles functionalized with elastin-like peptides (ELPs) at their N-terminal region. The target protein, CP-ELP, was expressed via E.coli, enabling encapsulation of the model drug DOX upon structural domain modification of the protein. The resulting nanoparticles exhibit uniform size distribution, facilitating efficient internalization by tumor cells and subsequent intracellular drug release, leading to enhanced antitumor efficacy. In addition, EVLP@DOX nanoparticles were found to activate immune response of tumor microenvironment in vivo, which further inhibiting tumor growth. Our designed nanoparticles have also demonstrated remarkable therapeutic effectiveness and favorable biological safety profiles in both murine melanoma and colorectal cancer models.

Establishment of a predictive model for breast cancer chemotherapy efficacy and prognosis based on immune microenvironment molecules.

Establishment of a predictive model for breast cancer chemotherapy efficacy and prognosis based on immune microenvironment molecules.

Compression OCT-elastography combined with speckle-contrast analysis as an approach to the morphological assessment of breast cancer tissue.

Currently, optical biopsy technologies are being developed for rapid and label-free visualization of biological tissue with micrometer-level resolution. They can play an important role in breast-conserving surgery guidance, detection of residual cancer cells, and targeted histological analysis. For solving these problems, compression optical coherence elastography (C-OCE) demonstrated impressive results based on differences in the elasticity of different tissue constituents. However, sometimes straightforward C-OCE-based differentiation is insufficient because of the similar stiffness of certain tissue components. We present a new automated approach to the rapid morphological assessment of human breast cancer based on the combined usage of C-OCE and speckle-contrast (SC) analysis. Using the SC analysis of structural OCT images, the threshold value of the SC coefficient was established to enable the separation of areas of adipose cells from necrotic cancer cells, even if they are highly similar in elastic properties. Consequently, the boundaries of the tumor bed can be reliably identified. The joint analysis of structural and elastographic images enables automated morphological segmentation based on the characteristic ranges of stiffness (Young's modulus) and SC coefficient established for four morphological structures of breast-cancer samples from patients post neoadjuvant chemotherapy (residual cancer cells, cancer stroma, necrotic cancer cells, and mammary adipose cells). This enabled precise automated detection of residual cancer-cell zones within the tumor bed for grading cancer response to chemotherapy. The results of C-OCE/SC morphometry highly correlated with the histology-based results (r =0.96-0.98). The combined C-OCE/SC approach has the potential to be used intraoperatively for achieving clean resection margins in breast cancer surgery and for performing targeted histological analysis of samples, including the evaluation of the efficacy of cancer chemotherapy.

Thymosin alpha 1 – Reimagine its broader applications in the immuno-oncology era

Thymosin alpha 1 (Tα1) is a highly conserved 28 amino-acid peptide naturally occurring in the thymus and plays critical roles in T cell maturity and differentiation. Its synthetic form, thymalfasin, has been approved by various regulatory agencies in the treatment of hepatitis B viral infection and as an enhancer of vaccine response in immune-compromised populations. In China, it has also widely utilized in patients with cancer and severe infections, as well as the emergency use during (Severe Acute Respiratory Syndrome)SARS and COVID-19 pandemic as an immune-regulator. Recent studies showed that Tα1 could significantly improve overall survival (OS) in patients with surgically resectable non-small cell lung cancer (NSCLC) and liver cancers in the adjuvant setting. For patients with locally advanced, unresectable NSCLC, Tα1 could significantly reduce chemoradiation-induced lymphopenia, pneumonia, and trending improvement of OS. Preclinical evidence are emerging to demonstrate that Tα1 may augment efficacy of cancer chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis and enhancing anti-tumor immunity by turning "cold-tumors" to "hot-tumors"; a protective role in reducing colitis caused by immune check-point inhibitors (ICIs). Potential enhancement of ICIs' clinical efficacies has also been indicated. ICIs have transformed ways treating patients with cancer but limitations such as relatively low response rates and certain safety issues remains. Given the roles of Tα1 in regulating cellular immunities and exceptional safety profiles demonstrated in decades clinical uses, we believe that it is plausible to explore implications of Tα1 the immune-oncology setting by combining with ICI-based therapeutic strategies. Background Activities of Tα1. Tα1 is a biological response modifier which activates various cells in the immune system [1-3]. Tα1 is therefore expected to have clinical benefits in disorders where immune responses are impaired or ineffective. These disorders include acute and chronic infections, cancers, and vaccine non-responsiveness. In severe sepsis, for example, sepsis-induced immunosuppression is increasingly recognized as the overriding immune dysfunction in these vulnerable patients [4] and there is now agreement that many patients with severe sepsis survive the first critical hours of the syndrome but eventually die later due to patients' immunosuppression which make the system difficulty to fight the primary bacterial infection, decreased resistance to secondary nosocomial infections, and reactivation of viral infections [5]. Tα1 has been shown to restore immune functions and help to reduce mortality in patients with severe sepsis.

CRGD-Functionalized Silk Fibroin Nanoparticles: A Strategy for Cancer Treatment with a Potent Unselective Naphthalene Diimide Derivative

Developing drug delivery systems to target cytotoxic drugs directly into tumor cells is still a compelling need with regard to reducing side effects and improving the efficacy of cancer chemotherapy. In this work, silk fibroin nanoparticles (SFNs) have been designed to load a previously described cytotoxic compound (NDI-1) that disrupts the cell cycle by specifically interacting with non-canonical secondary structures of DNA. SFNs were then functionalized on their surface with cyclic pentapeptides incorporating the Arg-Gly-Asp sequence (cRGDs) to provide active targeting toward glioma cell lines that abundantly express ανβ3 and ανβ5 integrin receptors. Cytotoxicity and selective targeting were assessed by in vitro tests on human glioma cell lines U373 (highly-expressing integrin subunits) and D384 cell lines (low-expressing integrin subunits in comparison to U373). SFNs were of nanometric size (d50 less than 100 nm), round shaped with a smooth surface, and with a negative surface charge; overall, these characteristics made them very likely to be taken up by cells. The active NDI-1 was loaded into SFNs with high encapsulation efficiency and was not released before the internalization and degradation by cells. Functionalization with cRGDs provided selectivity in cell uptake and thus cytotoxicity, with a significantly higher cytotoxic effect of NDI-1 delivered by cRGD-SFNs on U373 cells than on D384 cells. This manuscript provides an in vitro proof-of-concept of cRGD-silk fibroin nanoparticles' active site-specific targeting of tumors, paving the way for further in vivo efficacy tests.

Glutamine stabilizes myc via alpha-ketoglutarate and regulates paclitaxel sensitivity.

Metabolic reprogramming wherein the cancer cells exhibit altered energetics is a hallmark of cancer. Although recent discoveries have enhanced our understanding of tumor metabolism, the therapeutic utility of targeting tumor metabolism is not yet realized. Glutamine, a non-essential amino acid, plays a critical role in regulating tumor metabolism and provides an alternative tumor energy source. In this study, we investigate the molecular mechanism regulated by glutamine and elucidate if targeting glutamine metabolism would enhance the efficacy of cancer chemotherapy. Using clonogenic and cell cycle analysis, we found that deprivation of glutamine suppress the growth of cancer cells. Mechanistically we demonstrate that glutamine stabilizes myc by preventing its ubiquitination through alpha-ketoglutarate. Inhibition of glutamine metabolism enhanced the sensitivity of tumor cells to chemotherapeutic agent paclitaxel. Our results delineate the mechanism behind glutamine-induced myc stabilization, and they provide a viable strategy to target cancer with a glutamine metabolism inhibitor in the clinic.

Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics.

Cancer is a multifactorial, multi-stage disease, including complex cascades of signaling pathways—the cell growth governed by dysregulated and abrupt cell division. Due to the complexity and multi-regulatory cancer progression, cancer is still a challenging disease to treat and survive. The screening of extracts and fractions from plants and marine species might lead to the discovery of more effective compounds for cancer therapeutics. The isolated compounds and reformed analogs were known as future prospective contenders for anti-cancer chemotherapy. For example, Taxol, a potent mitotic inhibitor discovered from Taxus brevifolia, suppresses cell growth and arrest, induces apoptosis, and inhibits proliferation. Similarly, marine sponges show remarkable tumor chemo preventive and chemotherapeutic potential. However, there is limited research to date. Several plants and marine-derived anti-cancer compounds having the property to induce apoptosis have been approved for clinical trials. The anti-cancer activity kills the cell and slows the growth of cancer cells. Among cell death mechanisms, apoptosis induction is a more profound mechanism of cell death triggered by naturally isolated anti-cancer agents. Evading apoptosis is the major hurdle in killing cancer cells, a mechanism mainly regulated as intrinsic and extrinsic. However, it is possible to modify the apoptosis-resistant phenotype of the cell by altering many of these mechanisms. Various extracts and fractions successfully induce apoptosis, cell-cycle modulation, apoptosis, and anti-proliferative activity. Therefore, there is a pressing need to develop new anti-cancer drugs of natural origins to reduce the effects on normal cells. Here, we’ve emphasized the most critical elements: i) A better understanding of cancer progression and development and its origins, ii) Molecular strategies to inhibit the cell proliferation/Carcino-genesis, iii) Critical regulators of cancer cell proliferation and development, iv) Signaling Pathways in Apoptosis: Potential Targets for targeted therapeutics, v) Why Apoptosis induction is mandatory for effective chemotherapy, vi) Plants extracts/fractions as potential apoptotic inducers, vii) Marine extracts as Apoptotic inducers, viii) Marine isolated Targeted compounds as Apoptotic inducers (FDA Approved/treatment Phase). This study provides a potential therapeutic option for cancer, although more clinical studies are needed to verify its efficacy in cancer chemotherapy.

Ribociclib Inhibits P-gp-Mediated Multidrug Resistance in Human Epidermoid Carcinoma Cells.

The efficacy of cancer chemotherapy can be attenuated or abrogated by multidrug resistance (MDR) in cancer cells. In this study, we determined the effect of the CDK4/6 inhibitor, ribociclib (or LEE011), on P-glycoprotein (P-gp)-mediated MDR in the human epidermoid carcinoma MDR cell line, KB-C2, which is widely used for studying P-gp-mediated MDR in cancers. The incubation of KB-C2 cells with ribociclib (3–9 µM) increased the efficacy of colchicine, a substrate for P-gp. The cell expression of P-gp was down-regulated at both translation and transcription levels. Furthermore, ribociclib produced a 3.5-fold increase in the basal activity of P-gp ATPase, and the concentration required to increase basal activity by 50% (EC50) was 0.04 μM. Docking studies indicated that ribociclib interacted with the drug-substrate binding site of P-gp. The short-term and long-term intracellular accumulation of doxorubicin greatly increased in the KB-C2 cells co-cultured with ribociclib, indicating ribociclib inhibited the drug efflux activity of P-gp. The results of our study indicate that LEE011 may be a potential agent for combined therapy of the cancers with P-gp mediated MDR.

Considering therapy-induced senescence as a mechanism of tumour dormancy contributing to disease recurrence.

The capability of tumour cells to escape from therapy-induced senescence, as well as cell-non-autonomous functions of senescence, support the premise that senescence could serve as one pathway to tumour dormancy (among others that include quiescence and diapause) that is permissive for disease recurrence. Consequently, the pharmacologic targeting of senescent tumour cells could mitigate the risk for cancer resurgence, thereby enhancing the therapeutic efficacy of cancer chemotherapy.

Using mathematical modeling to estimate time-independent cancer chemotherapy efficacy parameters.

One of the primary cancer treatment modalities is chemotherapy. Unfortunately, traditional anti-cancer drugs are often not selective and cause damage to healthy cells, leading to serious side effects for patients. For this reason more targeted therapeutics and drug delivery methods are being developed. The effectiveness of new treatments is initially determined via in vitro cell viability assays, which determine the of the drug. However, these assays are known to result in estimates of that depend on the measurement time, possibly resulting in over- or under-estimation of the . Here, we test the possibility of using cell growth curves and fitting of mathematical models to determine the as well as the maximum efficacy of a drug ( ). We measured cell growth of MCF-7 and HeLa cells in the presence of different concentrations of doxorubicin and fit the data with a logistic growth model that incorporates the effect of the drug. This method leads to measurement time-independent estimates of and , but we find that is not identifiable. Further refinement of this methodology is needed to produce uniquely identifiable parameter estimates.

Design and synthesis of a star-like polymeric micelle modified with AS1411 aptamer for targeted delivery of camptothecin for cancer therapy

Improving of tumor targeting and decreasing side effects at normal cells of antitumor drugs are necessary to promote the cancer chemotherapy efficacy. Herein, we have synthesized a novel 21-arm star like diblock polymer of β-cyclodextrin-{poly(ε-caprolactone)-poly(2-aminoethylmethacrylate)}21 which decorated with nucleolin aptamer (AS1411). The diblock polymer was prepared by combined ROP with electron transfer atom transfer radical polymerization (ARGET ATRP) methods followed camptothecin (CPT) encapsulation with high entrapment efficiency (65%). Subsequently, the attachment of AS1411 aptamer via covalent bond led to the formation of the final product β-CD-(PCL-PAEMA)21/AS1411/CPT. In vitro drug release experiment demonstrated almost 50% of CPT was released in 72h at acidic tumoral environment. The data of cellular toxicity (MTT) showed that the final product remarkably enhanced cell death in MCF-7 and 4T1 cells while normal cells (L929) showed high viability toward the prepared complex. Also, the finding of flow cytometry analysis and fluorescence imaging indicated successful internalization of complex into the target cells but not the nontarget cells. The in vivo experiments revealed the fact that β-CD-(PCL-PAEMA)21/AS1411/CPT micelles showed high tumor inhibitory potential in comparison with free CPT. These findings exhibited the excellent ability of the novel star-like polymeric micelle with targeting agent for the targeted and effective delivery of CPT in cancer treatment.

Targeting UPR branches, a potential strategy for enhancing efficacy of cancer chemotherapy.

Cancer cells are often exposed to cell intrinsic stresses and environmental perturbations that may lead to accumulation of unfolded and/or misfolded proteins in the lumen of endoplasmic reticulum (ER), a cellular condition known as ER stress. In response to ER stress, the cells elicit an adaptive process called unfolded protein response (UPR) to cope with the stress, supporting cellular homeostasis and survival. The ER stress sensors inositol requiring protein 1α (IRE1α), eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK), and activating transcription factor 6 (ATF6) constitute the three branches of UPR to resolve ER stress. IRE1α, PERK, and ATF6 play an important role in tumor cell growth and survival. They are also involved in chemotherapy resistance of cancers. These have generated widespread interest in targeting these UPR branches for cancer treatment. In this review, we provide an overview of the role of IRE1α, PERK, and ATF6 in cancer progression and drug resistance and we summarize the research advances in targeting these UPR branches to enhance the efficacy of chemotherapy of cancers.