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Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
A chemosensitizer is an agent used to make tumor cells more sensitive to chemotherapeutic agents. Every day synthetic chemo sensitizers are being used in cancer chemotherapy and it has been becoming a serious concern that cancer is undergoing evolution and is slowly developing resistance to chemotherapy. Because certain types of cancers are developing resistance to synthetic chemo sensitizers, some natural products are under investigation for possible future use as chemosensitizers such as resveratrol, berberine, and bleomycin. Resveratrol continues to be studied as a chemo sensitizer for cancer chemotherapeutics. A study (Fulda et al., 2004) reported possible chemosensitization prospective of resveratrol. Resveratrol induces chemosensitization through modification and subsequent cessation of the cell cycle. Cessation of cell cycle lowers down the concentration of survivin (recombinant) protein, which at high concentration prevents apoptosis. Furthermore, resveratrol-triggered apoptosis is independent of p53 gene mutations. The study concluded that resveratrol could sensitize neuroblastoma, prostate carcinoma, breast carcinoma, pancreatic carcinoma, leukemia, and glioblastoma increasing the apoptotic possibility of certain drugs like taxol and actinomycin D (dactinomycin). Resveratrol could cause modification of p53 gene as well (Gatouillat et al., 2010). Resveratrol down-regulated cyclin D1/cdk4 and overexpressed p53 genes in vivo murine model of B16 melanoma which resulted in relatively higher survival rate. More research in this field was conducted to validate the chemosensitizing ability of resveratrol by modulation of cell survival proteins. Resveratrol could sensitize neoplastic cells by caspase activation and regulating NF-κβgenes (Buhrmann et al., 2015).
Amplification of anticancer efficacy by co-delivery of doxorubicin and lonidamine with extracellular vesicles
Published in Drug Delivery, 2022
Huizhen Li, Wan Xu, Fang Li, Ru Zeng, Xiuming Zhang, Xianwu Wang, Shaojun Zhao, Jian Weng, Zhu Li, Liping Sun
Small-molecule chemosensitizers can reverse cancer multidrug resistance (MDR) and improve the effect of chemotherapy drugs. Lonidamine (LND) is an inhibitor of hexokinaseII (HK), which is a key enzyme in the glycolysis pathway (Figure S1(B)). Cancer cells rely on aerobic glycolysis to produce ATP (Warburg effect). Thus, inhibiting the glycolysis pathway can reduce the energy supply of cancer cells and inhibit tumor growth. But the anticancer effect is limited using LND alone. Therefore, it is often used in combination with other anticancer drugs as a chemosensitizer (Floridi et al., 1981a,b). Li et al. (2002) found that the cell viability of HepG2 treated with DOX and LND for 24 h was reduced by 40% compared with doxorubicin alone. However, due to their small molecular weight and size, they are rapidly cleared by the body. Moreover, poor solubility and low permeability limited their accumulation in cancer cells (Sun et al., 2017).
Development of nanocubosomes co-loaded with dual anticancer agents curcumin and temozolomide for effective colon cancer therapy
Published in Drug Delivery, 2022
Yosif Almoshari, Haroon Iqbal, Anam Razzaq, Khalil Ali Ahmad, Muhammad Khalid Khan, Saad Saeed Alqahtani, Muhammad H. Sultan, Barkat Ali Khan
Adaptive treatment tolerance (ATT) is considered as one of the major obstacles in cancer therapy, which causes poor sensitivity in cancer cells to the chemotherapeutic drugs due to prolonged exposure (Zhao et al., 2014; Motevalli et al., 2019). ATT might be triggered by three processes, (i) the drugs failed to cross the plasma membrane (ii) the drugs easily exorcize from lysosomal environment of the cancer cells (iii) the activation of efflux pump or multidrug resistance (MDR) proteins which transport or escape the drugs from the cancer cells (Housman et al., 2014; Zhitomirsky & Assaraf, 2016). One potential strategy applied to overawed ATT is the administration of two or more chemotherapeutic drugs to the cancer cells together (C. Wang et al., 2013;). Chemotherapeutic drugs can be co-administered into cancer cells by two different approaches, i.e. sequential and simultaneous co-administration (Poradowski & Chrószcz, 2022). In sequential co-administration approach, cancer cells were first treated with chemosensitizers followed by the chemotherapeutic drug administration. Pretreatment of chemosensitizers significantly upsurges the efficiency of chemotherapeutic drugs in cancer cells (Benyettou et al., 2017). For example, erlotinib pretreatment blocked the epidermal growth factor (EGF) receptor and enhanced the therapeutic activity of doxorubicin against breast cancers (Lee et al., 2012). However, sequential approach is not always preferred for the co-administration of anticancer drugs. In contrast, simultaneous co-administration approach of chemotherapeutic drugs shows more therapeutic efficacy in advanced and resectable colorectal tumors as compared to sequential approach of co-administration for chemotherapeutic drugs (Ducreux et al., 2011; Fares et al., 2020). However, co-administration of chemotherapeutic drugs usually fails to attain its full therapeutic efficacy due to its poor water solubility, rapid clearance, and off-target toxicities. To combat this problem, chemotherapeutic drugs have been co-loaded into nanodrug delivery systems, which can enhance the therapeutic activity of chemotherapeutic drugs by enabling their enhanced cell penetration and intracellular distribution, and reducing their toxic effects on healthy cells (Bronze-Uhle et al., 2017; Li et al., 2021; Sohail et al., 2022).