Reyhaneh Farghadani

Breast cancer remains a significant global health challenge, with high incidence and mortality rates despite advancements in early detection and treatment. Multidrug resistance (MDR), particularly in aggressive subtypes like triple‐negative breast cancer (TNBC), continues to hinder effective therapy. MDR is primarily driven by the overexpression of ATP‐binding cassette (ABC) transporters such as P‐gp, BCRP, and MRP1. ABC transporters actively efflux chemotherapeutic agents, reducing their efficacy and complicating treatment outcomes. This narrative review explores the potential of natural products to modulate ABC transporters as a strategy to mitigate MDR in breast cancer. A literature search was conducted across Ovid Medline, PubMed, Scopus, Embase, Web of Science, and EBSCOhost. Articles underwent a two‐stage screening process (title and abstract and full text), with additional manual searches of reference lists. The results show that natural products derived from plants can inhibit ABC transporters through suppression of protein expression, downregulation of mRNA expression, and inhibition of drug efflux functions. Additionally, they target indirect regulatory pathways, such as NF‐κB, YB‐1, PI3K/Akt, and ATPase activity, further contributing to the reversal of MDR. These compounds work synergistically with chemotherapeutic agents like doxorubicin and paclitaxel to enhance drug retention and efficacy while reducing toxicity. This multifaceted approach highlights the potential of natural products as valuable adjunct therapies in breast cancer treatment, offering new strategies to overcome drug resistance and improve patient outcomes.

Breast cancer (BC) is the most prevalent cancer among women. Despite improvements in the detection and treatment of BC, drug resistance is widespread, making it the leading cause of cancer mortality in women. Long non-coding RNAs (lncRNAs) have been shown to play essential roles in regulating drug resistance in pre-clinical models. However, their clinical relevance remains largely unexplored. This review addresses this gap by identifying and examining lncRNAs with potential predictive value as biomarkers for drug resistance in BC cancer patients. A systematic search (last updated February 7, 2024) was conducted across five databases (Cochrane Library, Embase, PubMed, Scopus, and Web of Science) for research articles in English, published after 2010, involving BC patients who underwent treatment. Following the selection and review process, 66 studies were short-listed, and 185 unique lncRNAs linked to drug resistance in BC patients were identified. Notably, only five lncRNAs (BCAR4, CCAT2, DSCAM-AS1, GAS5, and H19) were reported in at least two independent studies, indicating the scarcity of replicated evidence in clinical cohorts. Receiver operating characteristic curve analysis for these five lncRNAs confirmed that BCAR4, GAS5, and H19 expression levels have prognostic potential for predicting chemotherapy response. However, further validation is required before lncRNAs can be effectively utilized as prognostic markers in a clinical setting.

Atezolizumab (TECENTRIQ®) and nivolumab (OPDIVO®) are both immunotherapeutic indications targeting programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1), respectively. These inhibitors hold promise as therapies for triple-negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) and have demonstrated encouraging results in reducing the progression and spread of tumors. However, due to their adverse effects and low response rates, the US Food and Drug Administration (FDA) has withdrawn the approval of atezolizumab in TNBC and nivolumab in HCC treatment. The withdrawals of atezolizumab and nivolumab have raised concerns regarding their effectiveness and the ability to predict treatment responses. Therefore, the current study aims to investigate the immunotherapy withdrawal of PD-1/PD-L1 inhibitors, specifically atezolizumab for TNBC and nivolumab for HCC. This study will examine both the structural and clinical aspects. This review provides detailed insights into the structure of the PD-1 receptor and its ligands, the interactions between PD-1 and PD-L1, and their interactions with the withdrawn antibodies (atezolizumab and nivolumab) as well as PD-1 and PD-L1 modifications. In addition, this review further assesses these antibodies in the context of TNBC and HCC. It seeks to elucidate the factors that contribute to diverse responses to PD-1/PD-L1 therapy in different types of cancer and propose approaches for predicting responses, mitigating the potential risks linked to therapy withdrawals, and optimizing patient outcomes. By better understanding the mechanisms underlying responses to PD-1/PD-L1 therapy and developing strategies to predict these responses, it is possible to create more efficient treatments for TNBC and HCC. Graphical Abstract

The pathogenesis of many diseases is most closely related to inappropriate apoptosis (either too little or too much) and cancer is one of the situations where too little apoptosis happens, leading to malignant cells that highly proliferate. Defects at any points along apoptotic pathways may lead to malignant transformation of the affected cells, tumor metastasis, and resistance to anti-cancer drugs. Several major molecular mechanisms are involved in the evasion of apoptosis in cancer initiation and progression. Bcl-2 family of proteins and caspases are the central players in the apoptotic mechanism and regulate cell death. Their imperfections cause to the deficient apoptotic signaling and thereby the inadequate apoptosis in cancer cells and eventually carcinogenesis. Strategies targeting these master regulators in carcinoma cells has been a major focus of interest in cancer studies. Therefore, despite being the cause of problem, apoptosis can be targeted in cancer therapy. This chapter provides a comprehensive review of apoptotic cell death and how deficiencies in apoptotic master regulators, caspases and Bcl-2 family proteins, influence carcinogenesis and can be targeted in cancer treatment.

Pancreatic cancer is one of the most devastating of all malignancies with poor prognosis and high mortality rates worldwide. Thymoquinone, plumbagin and juglone, which are naturally occurring quinones, have been reported for their promising anticancer effect on different cancer cells. However, their mechanism of action and antimetastatic effects are largely unknown against the human pancreatic cancer cell line (PANC‐1). In this study, the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) cytotoxicity assay revealed a dose‐dependent decrease of viability in quinone‐treated PANC‐1 cells. In addition, the assessment of changes in cells has demonstrated an occurrence of typical apoptotic morphology in treated PANC‐1 cells compared with control. Besides this, the apoptosis induction was further quantitatively confirmed through flow cytometry analysis. Furthermore, thymoquinone, plumbagin and juglone were evaluated for their influence on reactive oxygen species (ROS) generation through 2,7‐dichlorofluorescein diacetate (DCFDA) staining and they dramatically increased the intracellular ROS level in treated PANC‐1 cells, suggesting the critical role of ROS in their apoptosis induction. This study also demonstrated the wound healing potential of these compounds and inhibited PANC‐1 cell migration in a time‐dependent manner compared with control. This inhibition was correlated with reduced expression of matrix metalloproteinase‐9 (MMP‐9) in juglone‐treated cells detected through gelatin zymography. In conclusion, thymoquinone, plumbagin and juglone significantly inhibited cell growth and induced ROS‐mediated apoptosis in PANC‐1 cells. In addition, they could be potent antimetastatic agents due to their anti‐migratory effect against PANC‐1 human pancreatic cancer cells.

Female breast cancer is the world’s most prevalent cancer in 2020. Chemotherapy still remains a backbone in breast cancer therapy and is crucial in advanced and metastatic breast cancer treatment. The clinical efficiency of chemotherapy regimens is limited due to tumor heterogeneity, chemoresistance, and side effects. Chemotherapeutic drug combinations with natural products hold great promise for enhancing their anticancer efficacy. Curcumin is an ideal chemopreventive and chemotherapy agent owning to its multitargeting function on various regulatory molecules, key signaling pathways, and pharmacological safety. This review aimed to elucidate the potential role of curcumin in enhancing the efficacy of doxorubicin, paclitaxel, 5-fluorouracil, and cisplatin via combinational therapy. Additionally, the molecular mechanisms underlying the chemosensitizing activity of these combinations have been addressed. Overall, based on the promising therapeutic potential of curcumin in combination with conventional chemotherapy drugs, curcumin is of considerable value to develop as an adjunct for combination chemotherapy with current drugs to treat breast cancer. Furthermore, this topic may provide the frameworks for the future research direction of curcumin–chemotherapy combination studies and may benefit in the development of a novel therapeutic strategy to maximize the clinical efficacy of anticancer drugs while minimizing their side effects in the future breast cancer treatment.

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Despite the overall successes in breast cancer therapy, hormone-independent HER2 negative breast cancer, also known as triple negative breast cancer (TNBC), lacking estrogens and progesterone receptors and with an excessive expression of human epidermal growth factor receptor 2 (HER2), along with the hormone-independent HER2 positive subtype, still remain major challenges in breast cancer treatment. Due to their poor prognoses, aggressive phenotype, and highly metastasis features, new alternative therapies have become an urgent clinical need. One of the most noteworthy phytochemicals, curcumin, has attracted enormous attention as a promising drug candidate in breast cancer prevention and treatment due to its multi-targeting effect. Curcumin interrupts major stages of tumorigenesis including cell proliferation, survival, angiogenesis, and metastasis in hormone-independent breast cancer through the modulation of multiple signaling pathways. The current review has highlighted the anticancer activity of curcumin in hormone-independent breast cancer via focusing on its impact on key signaling pathways including the PI3K/Akt/mTOR pathway, JAK/STAT pathway, MAPK pathway, NF-ĸB pathway, p53 pathway, and Wnt/β-catenin, as well as apoptotic and cell cycle pathways. Besides, its therapeutic implications in clinical trials are here presented.