Efficacy Of Chemotherapy Drugs Research Articles

Self-Supplied Reactive Oxygen Species-Responsive Mitoxantrone Polyprodrug for Chemosensitization-Enhanced Chemotherapy under Moderate Hyperthermia.

Currently, the secondary development and modification of clinical drugs has become one of the research priorities. Researchers have developed a variety of TME-responsive nanomedicine carriers to solve certain clinical problems. Unfortunately, endogenous stimuli such as reactive oxygen species (ROS), as an important prerequisite for effective therapeutic efficacy, are not enough to achieve the expected drug release process, therefore, it is difficult to achieve a continuous and efficient treatment process. Herein, a self-supply ROS-responsive cascade polyprodrug (PMTO) is designed. The encapsulation of the chemotherapy drug mitoxantrone (MTO) in a polymer backbone could effectively reduce systemic toxicity when transported in vivo. After PMTO is degraded by endogenous ROS of the TME, another part of the polyprodrug backbone becomes cinnamaldehyde (CA), which can further enhance intracellular ROS, thereby achieving a sustained drug release process. Meanwhile, due to the disruption of the intracellular redox environment, the efficacy of chemotherapy drugs is enhanced. Finally, the anticancer treatment efficacy is further enhanced due to the mild hyperthermia effect of PMTO. In conclusion, the designed PMTO demonstrates remarkable antitumor efficacy, effectively addressing the limitations associated with MTO.

Gambogic Acid Lysinate-induced Cervical Cancer SiHa Cells Apoptosis in vitro and in vivo.

Surgical resection and chemotherapy are the primary treatment options for cervical cancer; however, efficacy of chemotherapy drugs is limited by drug resistance. There is an urgent need to find new compounds. Gambogic acid lysinate (GAL), a new compound made from gambogic acid and lysine, has good anti-tumor activity, however, the effect of GAL on cervical cancer remains undetermined. The present study sought to explore the anti-tumor activity of GAL in SiHa cells. Cell viability was detected by means of an MTT assay, a cell growth curve was drawn with Microsoft Excel 2010, the cell cycle and cell apoptosis were evaluated by flow cytometry, and Western blotting was employed to explore the mechanism of GAL. Additionally, the in vivo anti-tumor activity of GAL was studied through a xenograft tumor model in nude mice. GAL inhibited the proliferation of both SiHa cells (IC50 was 0.83 μmol/l and 0.77 μmol/l respectively for 48 h and 72 h) and HeLa cells (IC50 did not reach). In SiHa cells, GAL (1 and 2 μmol/l) inhibited cell proliferation and 2 μmol/l GAL could also induce cell apoptosis and decrease the number of S phase. Both 1 and 2 μmol/l GAL inhibited SiHa cells invasion and increased the number of G0/G1 phase. The results of Western blot assay demonstrated that P53 and P21 were involved in SiHa cells S phase arrest and BCL-2 and BAX were involved in SiHa cells apoptosis. In vivo study showed that the growth of SiHa cell xenograft tumors was inhibited via cell apoptosis induced by GAL (2.5 mg/kg body weight), however, GAL (2.5 mg/kg body weight) had no significant effect on weight gain of mice. GAL induced SiHa cells apoptosis by BCL-2 and BAX pathway and SiHa cells S phase arrest by P53 and P21 pathway in vitro and inhibited the growth of SiHa cell xenograft tumors.

Tumor Cell Distinguishable Nanomedicine Integrating Chemotherapeutic Sensitization and Protection

Theoretically, with a high enough drug dosage, cancer cells could be eliminated. However, the dosages that can be administered are limited by the therapeutic efficacy and side effects of the given drug. Herein, a nanomedicine integrating chemotherapeutic sensitization and protection was developed to relieve the limitation of administration dosage and to improve the efficacy of chemotherapy. The nanomedicine was endowed with the function of synergistically controlled release of CO and drugs under near-infrared (NIR) light irradiation. CO photo-induced release system (COPIRS) was synthesized by constructing an electron excitation–electron transfer group–electron-induced CO release structure and was used as the hydrophobic part, and then hydrophilic polymer (polyethylene glycol; PEG) was introduced by a thermal-responsive groups (DA group), forming a near-infrared-induced burst-release nanocarrier. In vitro and in vivo experiments showed that the nanomedicine can distinguish between tumor and normal cells and regulates the resistance of these different cells through the controlled release of carbonic oxide (CO), simultaneously enhancing the efficacy of chemotherapy drugs on tumor cells and chemotherapeutic protection on normal cells. This strategy could solve the current limitations on dosages due to toxicity and provide a solution for tumor cure by chemotherapy.

JAK2/STAT3 inhibitor reduced 5-FU resistance and autophagy through ATF6-mediated ER stress

Drug resistance seriously limits the efficacy of chemotherapy drugs and hinders successful treatment in patients with gastric cancer. Endoplasmic reticulum (ER) and autophagy are recognized to be one of the mechanisms involving the drug resistance of gastric cancer. The mechanisms of action of JAK2/STAT3 pathway were investigated in AGS cells with drug resistance of 5-fluorouracil (5-FU) by corresponding inhibitors. We firstly analyzed the effects of JAK2/STAT3 inhibitor on the expression of drug resistance genes, autophagy markers, and ER stress-related markers on AGS/5-FU cells by Western blot. Whether JAK2/STAT3 pathway regulated the transcription of ATF6 was investigated through luciferase reporter assay. The expression of LC3B was detected by immunofluorescence assay. Next, ER stress inhibitor and ATF6 overexpression plasmid were respectively used to treat AGS/5-FU cells for analyzing whether JAK2/STAT3 pathway regulated ER stress. The results showed that JAK2 inhibitor or STAT3 inhibitor significantly altered the expression of these proteins and suppressed the activities of ATF6 promoter. Intriguingly, ATP6 overexpression could markedly reverse their effects. Moreover, similar effects to JAK2 inhibitor or STAT3 inhibitor appeared in ER stress inhibitor-treated group. These findings indicated that the involvement of JAK2/STAT3 pathway in regulating ER stress affected the 5-FU resistance of AGS cells and autophagy, which was mediated by ATF6. Targeting JAK2/STAT3 pathway could be a potential approach to decrease the 5-FU resistance of gastric cancer and enhance the sensitivity of gastric cancer to 5-FU. Additionally, our study offers new insights into the molecular mechanisms underlying the resistance of gastric cancer to 5-FU.

Gadolinium Oxide Nanoparticles Enhance the Cytotoxicity of Chemotherapeutic Drugs by Blocking Autophagic Flux in Human Ovarian Cancer Cells

Background: During chemotherapy, drugs can damage cancer cells’ DNA and cytomembrane structure, and then induce cell death. However, autophagy can increase the chemotherapy resistance of cancer cells, reducing the effect of chemotherapy. Objective: To block the autophagic flux in cancer cells, it is vital to enhance the anti-cancer efficacy of chemotherapy drugs; for this purpose, we test the gadolinium oxide nanoparticles (Gd2O3 NPs)’ effect on autophagy. Methods: The cytotoxicity of Gd2O3 NPs on HeLa cells was evaluated by a (4,5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide assay. Then, monodasylcadaverine staining, immunofluorescence, immunoblot, and apoptosis assay were conducted to evaluate the effect of Gd2O3 NPs on autophagy and efficacy of chemotherapy drugs in human ovarian cancer cells. Results: We found that Gd2O3 NPs, which have great potential for use as a contrast agent in magnetic resonance imaging, could block the late stage of autophagic flux in a dose-dependent manner and then cause autophagosome accumulation in HeLa cells. When co-treated with 8 μg/mL Gd2O3 NPs and 5 μg/mL cisplatin, the number of dead HeLa cells increased by about 20% compared with cisplatin alone. We observed the same phenomenon in cisplatin-resistant COC1/DDP cells. Conclusion: We conclude that Gd2O3 NPs can block the late stage of autophagic flux and enhance the cytotoxicity of chemotherapeutic drugs in human ovarian cancer cells. Thus, the nanoparticles have significant potential for use in both diagnosis and therapy of solid tumor.

Mechanism of the Notch signaling pathway in enhancing the efficacy of chemotherapy drugs in osteosarcoma.

Osteosarcoma is the most common malignant tumors of bone. Since 1970s, researchers had used chemotherapy drugs to treat osteosarcoma. However, multidrug resistance is a major adverse reaction that affects the efficacy of chemotherapy drugs, leading to the reduced survival rate of osteosarcoma patients. The Notch signaling pathway plays an important role in osteosarcoma proliferation, which affects tumor resistance by reducing intracellular drug accumulation, regulating epithelial-mesenchymal transition, dysregulating microRNA, disrupting the expression of apoptosis genes, and regulating tumor stem cells.

PEGylated-PLGA Nanoparticles Coated with pH-Responsive Tannic Acid-Fe(III) Complexes for Reduced Premature Doxorubicin Release and Enhanced Targeting in Breast Cancer.

Biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) have been widely used as delivery vehicles for chemotherapy drugs. However, premature drug release in PLGA NPs can damage healthy tissue and cause serious adverse effects during systemic administration. Here, we report a tannic acid-Fe(III) (FeIII-TA) complex-modified PLGA nanoparticle platform (DOX-TPLGA NPs) for the tumor-targeted delivery of doxorubicin (DOX). A PEGylated-PLGA inner core and FeIII-TA complex outer shell were simultaneously introduced to reduce premature drug release in blood circulation and increase pH-triggered drug release in tumor tissue. Compared to the unmodified NPs, the initial burst rate of DOX-TPLGA NPs was significantly reduced by nearly 2-fold at pH 7.4. Moreover, the cumulative drug release rate at pH 5.0 was 40% greater than that at pH 7.4 due to the pH-response of the FeIII-TA complex. Cellular studies revealed that the TPLGA NPs had enhanced drug uptake and superior cytotoxicity of breast cancer cells in comparison to free DOX. Additionally, the DOX-TPLGA NPs efficiently accumulated in the tumor site of 4T1-bearing nude mice due to the enhanced permeability and retention (EPR) effect and reached a tumor inhibition rate of 85.53 ± 8.77% (1.31-fold versus DOX-PLGA NPs and 3.12-fold versus free DOX). Consequently, the novel TPLGA NPs represent a promising delivery platform to enhance the safety and efficacy of chemotherapy drugs.

Advances in basic research of Chinese medicine monomers and active ingredients in the treatment of pancreatic cancer

This article reviews the basic research on the treatment of pancreatic cancer from the aspects of Chinese medicine monomer and active ingredients, in order to provide a useful reference for the in-depth study of traditional Chinese medicine for pancreatic cancer. Chinese medicine has achieved remarkable effects in the treatment of pancreatic cancer, which can enhance the efficacy of chemotherapy drugs, alleviate clinical symptoms, reduce adverse reactions, and improve quality of life. The mechanism needs further study. Key words: Chemical compositions (TCD); Chinese medicine monomer; Active ingredient; Pancreatic cancer; Animal experimentation; Basic research; Review

Abstract B46: Tetra-O-methyl nordihydroguaiaretic acid broadly suppresses cancer metabolism and synergistically induces strong anticancer activity in combination with Etoposide, Rapamycin and UCN-01

Abstract We have been developing an anticancer drug, Tetra-O-methyl nordihydroguaiaretic acid (M4N), for many years. M4N is currently in Phase I/II clinical trials in patients with various advanced cancer. The results of these clinical trials so far indicate that M4N has a certain degree of anticancer activity, but was unable to induce remission in any of these patients with advanced cancers. One of the most frequently attempted strategy to increase anticancer efficacy of chemotherapy drugs is combination treatment with one or more appropriately selected drugs. An important finding from the clinical trials with M4N is that the toxicity of the drug was very low. Patients were able to tolerate high doses of M4N with minimal side-effects, which make this drug very suitable for being use in multidrug treatments (for instance the LD50 of M4N for mice is greater than 1000mg/kg while that of NDGA, a parental compound for M4N, is only 75mg/kg). In this study the ability of M4N to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines including several pancreatic cell lines (AsPC-1, CAK24, Panc1.98, and Panc215). In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP prostatic, AsPC-1 pancreatic, and L428 leukemic cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination treatments for cancers of various origins including pancreas. Citation Format: Kotohiko Kimura, Ru Chih C. Huang.{Authors}. Tetra-O-methyl nordihydroguaiaretic acid broadly suppresses cancer metabolism and synergistically induces strong anticancer activity in combination with Etoposide, Rapamycin and UCN-01. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B46.

Correlation between Gene Variants, Signaling Pathways, and Efficacy of Chemotherapy Drugs against Colon Cancers.

Efficacies, toxicities, and resistance mechanisms of chemotherapy drugs, such as oxaliplatin and 5-fluorouracil (5-FU), vary widely among various categories and subcategories of colon cancers. By understanding the differences in the drug efficacy and resistance at the level of protein–protein networks, we identified the correlation between the drug activity of oxaliplatin/5-FU and gene variations from the US National Cancer Institute-60 human cancer cell lines. The activity of either of these drugs is correlated with specific amino acid variant(s) of KRAS and other genes from the signaling pathways of colon cancer progression. We also discovered that the activity of a non-DNA-binding novel platinum drug, phosphaplatin, is comparable with oxaliplatin and 5-FU when it was tested against colon cancer cell lines. Our strategy that combines the knowledge from pharmacogenomics across cell lines with the molecular information from specific cancer cells is beneficial for predicting the outcome of a possible combination therapy for personalized treatment.

Sunflower Polymers for Folate-Mediated Drug Delivery.

Polymeric delivery vehicles can improve the safety and efficacy of chemotherapy drugs by facilitating preferential tumor delivery. Polymer-drug conjugates are especially attractive carriers because additional formulation steps are not required during manufacturing, and drug release profiles can be altered based on linker choice. For clinical translation, these vehicles should also be reproducibly and controllably synthesized. Recently, we reported the development of a class of materials called "sunflower polymers," synthesized by controlled radical polymerization of hydrophilic "petals" from a cyclic multimacroinitiator "core". This synthesis strategy afforded control over the size of the polymer nanostructures based on their petal polymerization time. In this work, we demonstrate that particle size can be further tuned by varying the degree of polymerization of the cyclic core in addition to that of the petals. Additionally, we investigate the application of these materials for tumor-targeted drug delivery. We demonstrate that folate-targeted, doxorubicin-conjugated sunflower polymers undergo receptor-mediated uptake into cancer cells and pH-triggered drug release leading to cytotoxicity. These materials are attractive as drug carriers due to their discrete and small size, shielded drug cargo that can be triggered for release, and relative ease of synthesis.

Improving the efficacy of chemotherapy drugs for the treatment of triple-negative breast cancers.

107 Background: Approximately 15-20% of all breast cancers account for triple-negative breast cancers that exhibit aggressive, distinct metastatic pattern and poor prognosis. More than 50% of patients with triple negative breast cancers develop chemoresistance and do not respond to chemotherapeutic drugs, leading to early relapse and shorter survival. Understanding the mechanisms underlying such resistance is therefore crucial for the development of new, efficacious cancer drugs. Methods: Through high-throughput miRNA inhibitor library screens, we have identified miRNA inhibitors that sensitize resistant triple negative breast cancer cells to paclitaxel, a drug commonly used to treat triple negative breast cancers. Results: Through high-throughput miRNA inhibitor library screens, we have identified miRNA inhibitors that sensitize resistant triple negative breast cancer cells to paclitaxel, a drug commonly used to treat triple negative breast cancers. Since miRNAs are endogenously expressed and can be easily manipulated using synthetic oligoribonucleotides, we believe that they represent more attractive targets than the single gene or gene product that is the target of conventional cancer treatments that are typically prone to drug resistance. Supporting this, we have recently demonstrated that miRNAs can be systemically delivered to treat breast cancer lung metastasis without any hepatotoxicity. In addition to being a potent therapeutic regimen, our preliminary analyses reveal that miRNAs can be bonafide early prognostic markers to monitor treatment response to specific drugs in triple-negative breast cancers. Conclusions: Taken together, these findings suggest that miRNA can serve as potent therapeutic adjuvants and although the data content of miRNA profiles is far less than that of gene expression profiles, by virtue of their ability to modulate entire spectrum of genes and pathways miRNAs have potential to be better classifiers for the prognosis and response to treatment of cancers. We believe that the identification of miRNAs that mediate chemoresistance could lead to more efficient treatment selection at the patient level and an improved response rates at the population level.

Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker females with pulmonary adenocarcinoma.

10527 Background: Epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement was found not only predict the efficacy of targeted drugs, but also associate with the efficacy of chemotherapy drugs in non-small cell lung cancer (NSCLC) patients. We investigated the relationship of EGFR mutation status or ALK rearrangement and DNA repair or synthesis genes, such as excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS) and breast cancer gene one (BRCA1) gene expression, as a potential explanation for these observations. Methods: In this surgical series, 104 resected lung adenocarcinomas from nonsmoker females were analyzed concurrently for the EGFR mutation, ALK rearrangement status and mRNA expression of ERCC1, RRM1, TS and BRCA1 genes. EGFR mutation detection was performed by the method of ADx-ARMS, ALK rearrangement was detected by PCR and the mRNA expression of different genes were tested using the method of real-time PCR. Results: 73 (70.2%) patients harbored EGFR mutations and 10 (9.6%) had ALK rearrangement. The ERCC1 mRNA level in patients with EGFR mutation was 3.44±1.94×10-3 , which is significantly lower than in the patients with ALK positive and both negative(4.60±1.95×10-3 and 4.95±2.33×10-3 respectively, P=0.010). While the TS mRNA levels were significantly lower in the patients with EGFR mutation(1.15±1.38×10-3 VS 2.69±3.97×10-3, P=0.006) or ALK positive (1.21±0.78×10-3VS 2.69±3.97×10-3, P=0.020) than in patients with both negative. Conclusions: NSCLC specimens harboring activating EGFR mutations are more likely to express low ERCC1 and TS mRNA levels, while NSCLC patients with ALK rearrangement are more likely to express low TS mRNA levels, which could be helpful to select a proper chemotherapy regimen for NSCLC patients with known EGFR mutation or ALK fusion status.

Abstract 5462: Enhancing efficacy of drugs by targeting CXCR2 receptor signaling for the treatment of malignant breast cancer

Abstract Breast cancer is the second most common cause of cancer death in women in the United States after lung cancer and is responsible for more than 40,000 deaths each year. Many challenges exist in the current management of advanced stage breast cancer as there are fewer recognized therapeutic strategies, often due to therapy resistance. Recent reports suggest that malignant cells that survive initial chemo- and radiation therapy often express inflammatory cytokines, which provides survival benefit making tumors resistant to further chemotherapy. The specific objective of the study is to develop strategy to manipulate chemokine-chemokine receptor network for effective therapy with limited toxicity against drug-resistant breast cancer. We investigated whether modulation of CXCR2-dependent signaling in malignant mammary tumor enhances therapeutic efficacy of chemotherapy drugs. We used mammary tumor cells expressing different levels of CXCR2 (Cl66-wt and Cl66-shCXCR2) and examined their response to Paclitaxel and Doxorubicin. We observed significant enhancement of paclitaxel and doxorubicin-mediated toxicity at concentrations 5 and 10nM in Cl66-shCXCR2 cells as compared to Cl66-wt cells. Moreover, the expression of CXCL1, a CXCR2 ligand, was increased in paclitaxel and doxorubicin treated mammary tumor cells. Paclitaxel and doxorubicin induced CXCL-1 levels was significantly lower in Cl66-shCXCR2 cells as compared to Cl66-wt cells. In vivo studies using wild type and knockdown cells showed no significant difference in the tumor growth. However, we observed a difference in the tumor growth between wild type and knockdown tumors in mice treated with 10mg/kg concentration of paclitaxel for 3 weeks after starting the treatment. When these studies were further extended there wasn't any difference between the two groups. Furthermore, we extended these studies using human breast cancer cell lines (MDA-MB231, MDA-MET, and SKBR3). MDA-MB231 and MDA-MET are triple negative and considered to be more metastatic and drug resistant than SKBR3 which is HER2-over expressing cell line. We observed differential expression of CXCR2 and its ligands in these cells. Our observation also showed significant difference in the paclitaxel and doxorubicin-mediated inhibitory response in MDA-MB231 and MDA-MET cells as compared to SKBR3 cells. Together these studies demonstrate that manipulating CXCR2-dependent activity in malignant breast cancer cells significantly enhanced therapeutic efficacy of paclitaxel and doxorubicin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5462.

Trumped Treatment?: BPA Blocks Effects of Breast Cancer Chemotherapy Drugs

Widespread human exposure to the chemical bisphenol A (BPA) has resulted from its use in a diverse array of consumer products. Research on the potential health effects of BPA has focused on the chemical’s ability to mimic or block natural estrogen. In animal studies, prenatal exposure to BPA increased susceptibility to mammary cancer in adulthood. However, studies of adult animals and cell cultures have had mixed results, and even less certain is how BPA might influence established breast cancer and its treatment. A new cell culture study is the first to show that BPA, at concentrations comparable to those found in the general population, reduces the efficacy of chemotherapy drugs in breast cancer cells, apparently by altering expression of proteins involved in apoptosis, or programmed cell death [EHP 117:175–180; LaPensee et al.]. The study used estrogen-responsive T47D cells and estrogen-insensitive MDA-MB-468 cells. Cells were pretreated with BPA and then incubated alone or with one of several concentrations of added doxorubicin, cisplatin, or vinblastine, commonly used chemotherapy drugs. BPA concentrations (1 and 10 nM) were comparable to levels documented in human milk and blood (0.5–40 nM). In some experiments, BPA pretreatment was preceded by addition of either ICI or PHTPP, compounds that block classical estrogen receptor-α and -β (ERα and ERβ, respectively). In addition to assessing cell survival, the researchers determined genetic expression and concentrations of the antiapoptotic proteins Bcl-2, Bcl-xL, and survivin, as well as classical and nonclassical estrogen receptors. The researchers found in T47D cells that BPA partially or completely blocked the effects of all doses of doxorubicin and cisplatin but only the lowest dose of vinblastine, with similar results in MDA-MB-468 cells. BPA by itself bolstered cell viability (i.e., chemoresistance) in T47D cells but not in MDA-MB-468 cells. Neither ICI nor PHTPP affected the ability of BPA to block doxorubicin’s actions in T47D cells, and BPA was able to mediate the drugs’ effects in MDA-MB-468 cells. These observations together suggest that BPA does not act via ERα or ERβ, helping to account for its effects on ER-insensitive cells. Given previous research that demonstrates a high binding affinity of estrogen-related receptor-γ (ERRγ) to BPA [EHP 116:32–38 (2008)], the researchers speculate that ERRγ, expressed by both cell lines in their study, is the most likely target for BPA binding. Based on their finding that BPA combined with doxorubicin increased levels of Bcl-2 and Bcl-xL, the researchers conclude that derailment of apoptosis could be a mechanism—perhaps common to all three drugs—by which BPA may inhibit the efficacy of breast cancer drugs. Both BPA binding to ERRγ and the compound’s role in apoptosis should be further examined in future research.