Overcoming Chemoresistance: Altering pH of Cellular Compartments by Chloroquine and Hydroxychloroquine

Resistance to the anti-cancer effects of chemotherapeutic agents (chemoresistance) is a major issue for people living with cancer and their providers. A diverse set of cellular and inter-organellar signaling changes have been implicated in chemoresistance, but it is still unclear what processes lead to chemoresistance and effective strategies to overcome chemoresistance are lacking. The anti-malaria drugs, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are being used for the treatment of various cancers and CQ and HCQ are used in combination with chemotherapeutic drugs to enhance their anti-cancer effects. The widely accepted anti-cancer effect of CQ and HCQ is their ability to inhibit autophagic flux. As diprotic weak bases, CQ and HCQ preferentially accumulate in acidic organelles and neutralize their luminal pH. In addition, CQ and HCQ acidify the cytosolic and extracellular environments; processes implicated in tumorigenesis and cancer. Thus, the anti-cancer effects of CQ and HCQ extend beyond autophagy inhibition. The present review summarizes effects of CQ, HCQ and proton pump inhibitors on pH of various cellular compartments and discuss potential mechanisms underlying their pH-dependent anti-cancer effects. The mechanisms considered here include their ability to de-acidify lysosomes and inhibit autophagosome lysosome fusion, to de-acidify Golgi apparatus and secretory vesicles thus affecting secretion, and to acidify cytoplasm thus disturbing aerobic metabolism. Further, we review the ability of these agents to prevent chemotherapeutic drugs from accumulating in acidic organelles and altering their cytosolic concentrations.

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Herbal Medicine Goshajinkigan Prevents Paclitaxel-Induced Mechanical Allodynia without Impairing Antitumor Activity of Paclitaxel

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/849754 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Muh. Akbar Bahar ◽

Tsugunobu Andoh ◽

Keisuke Ogura ◽

Yoshihiro Hayakawa ◽

Ikuo Saiki ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Herbal Medicine ◽

Tumor Growth ◽

Mechanical Allodynia ◽

Chemotherapeutic Agents ◽

Antitumor Action ◽

Effective Strategies ◽

Anti Cancer ◽

Mammary Fat Pad ◽

4T1 Cells

Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of commonly used chemotherapeutic agents. However, there are no effective strategies to treat the neuropathy. We examined whether Goshajinkigan, a herbal medicine, would prevent paclitaxel-induced allodynia without affecting the anticancer action in mice. Murine breast cancer 4T1 cells were inoculated into the mammary fat pad. Paclitaxel (10 and 20 mg/kg, intraperitoneal, alternate day from day 7 postinoculation) inhibited the tumor growth, and Goshajinkigan (1 g/kg, oral, daily from day 2 postinoculation) did not affect the antitumor action of paclitaxel. Mechanical allodynia developed in the inoculated region due to tumor growth and in the hind paw due to paclitaxel-induced neuropathy. Paclitaxel-induced allodynia was markedly prevented by Goshajinkigan, although tumor-associated allodynia was not inhibited by Goshajinkigan. These results suggest that Goshajinkigan prevents paclitaxel-induced peripheral neuropathy without interfering with the anti-cancer action of paclitaxel.

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A Systematic Review of Biosynthesized Metallic Nanoparticles as a Promising Anti-Cancer-Strategy

Cancers ◽

10.3390/cancers13112818 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2818

Author(s):

Anisa Andleeb ◽

Aneeta Andleeb ◽

Salman Asghar ◽

Gouhar Zaman ◽

Muhammad Tariq ◽

...

Keyword(s):

Side Effects ◽

Metallic Nanoparticles ◽

Causes Of Death ◽

Cost Effective ◽

Oxygen Species ◽

Chemotherapeutic Drugs ◽

Future Prospects ◽

Anti Cancer ◽

Cellular Compartments ◽

Normal Cell Cycle

Cancer is one of the foremost causes of death worldwide. Cancer develops because of mutation in genes that regulate normal cell cycle and cell division, thereby resulting in uncontrolled division and proliferation of cells. Various drugs have been used to treat cancer thus far; however, conventional chemotherapeutic drugs have lower bioavailability, rapid renal clearance, unequal delivery, and severe side effects. In the recent years, nanotechnology has flourished rapidly and has a multitude of applications in the biomedical field. Bio-mediated nanoparticles (NPs) are cost effective, safe, and biocompatible and have got substantial attention from researchers around the globe. Due to their safe profile and fewer side effects, these nanoscale materials offer a promising cure for cancer. Currently, various metallic NPs have been designed to cure or diagnose cancer; among these, silver (Ag), gold (Au), zinc (Zn) and copper (Cu) are the leading anti-cancer NPs. The anticancer potential of these NPs is attributed to the production of reactive oxygen species (ROS) in cellular compartments that eventually leads to activation of autophagic, apoptotic and necrotic death pathways. In this review, we summarized the recent advancements in the biosynthesis of Ag, Au, Zn and Cu NPs with emphasis on their mechanism of action. Moreover, nanotoxicity, as well as the future prospects and opportunities of nano-therapeutics, are also highlighted.

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Combination Therapy of Cisplatin and Other Agents for Osteosarcoma: A Review

Current Cancer Therapy Reviews ◽

10.2174/1573394716999201016160946 ◽

2020 ◽

Vol 16 ◽

Author(s):

Mohamad Zahid Kasiram ◽

Hermizi Hapidin ◽

Hasmah Abdullah ◽

Azlina Ahmad ◽

Sarina Sulong

Keyword(s):

Radiation Therapy ◽

Survival Rate ◽

Chemotherapeutic Agents ◽

New Combination ◽

Rapid Progression ◽

Combination Regimen ◽

Chemotherapeutic Drugs ◽

Primary Bone Tumor ◽

Phytochemical Compounds

Background: Osteosarcoma is the most common type of primary bone tumor in children and adolescents, which is associated with rapid progression and poor prognosis. Multimodal therapy is the most common approach utilized for osteosarcoma management, such as the application of chemotherapy in combination with surgery or radiation therapy. Cisplatin is one of the predominantly used chemotherapeutic agents for osteosarcoma. Optimally, it is employed in combination with other chemotherapeutic drugs along with surgery or radiation therapy. Despite the availability of numerous treatment approaches, patient survival rate has not definitively improved over the past three decades. Methods: We summarized all findings regarding the combination of cisplatin with other chemotherapeutic agents as well as with phytochemical compounds. Results: A combination of cisplatin with phytochemical compound synergistically enhances the killing effect of cisplatin on osteosarcoma cells with fewer side effects compared to combination with other chemotherapeutic agents. Conclusion: Conclusively, a combination of cisplatin with selected chemotherapeutic drugs, has been shown to be effective. However, the unchanged survival rate urges for the search of a new combination regimen. As a collaborative effort to substantiate the therapeutic efficacy, the combination with phytochemical compounds shows a promising response both in vitro as well as in the preclinical study.

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Exploring Nanoemulsion for Liver Cancer Therapy

Current Cancer Therapy Reviews ◽

10.2174/1573394716666200302123336 ◽

2020 ◽

Vol 16 (4) ◽

pp. 260-268

Author(s):

Tanmay Upadhyay ◽

Vaseem A. Ansari ◽

Usama Ahmad ◽

Nazneen Sultana ◽

Juber Akhtar

Keyword(s):

Cancer Therapy ◽

Liver Cancer ◽

Treatment Plan ◽

Chemotherapeutic Drugs ◽

Drug Delivery Vehicles ◽

Chronic Hepatitis B Virus ◽

Anti Cancer ◽

B Virus ◽

Delivery Vehicles ◽

Liquid Dosage Form

Cancer is a leading cause of mortality worldwide, accounting for 8.8 million deaths in 2015. Among these, at least 0.78 million people died of liver cancer alone. The recognized risk factors for liver cancer include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, exposure to dietary aflatoxin, fatty liver disease, alcohol-induced cirrhosis, obesity, smoking, diabetes, and iron overload. The treatment plan for early diagnosed patients includes radiation therapy, tumour ablation, surgery, immunotherapy, and chemotherapy. Some sort of drug delivery vehicles has to be used when the treatment plan is targeted chemotherapy. Nanoemulsions are a class of biphasic liquid dosage form which are mixtures of oil and water stabilized by a surfactant. They are either transparent or bluish in hue and serve as a wonderful carrier system for chemotherapeutic drugs. These vehicles have a particle size in the range of 20-200 nm allowing them to be delivered successfully in the deepest of tissues. Recent publications on nanoemulsions reveal their acceptance and a popular choice for delivering both synthetic and herbal drugs to the liver. This work focuses on some anti-cancer agents that utilized the advantages of nanoemulsion for liver cancer therapy.

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

Current Nanoscience ◽

10.2174/1573413716666200313155239 ◽

2020 ◽

Vol 16 ◽

Author(s):

Zhixiong Xie ◽

Tianyu Zhang ◽

Cheng Zhong

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Hela Cells ◽

Late Stage ◽

Ovarian Cancer Cells ◽

Oxide Nanoparticles ◽

Autophagic Flux ◽

Human Ovarian Cancer ◽

Chemotherapeutic Drugs ◽

Chemotherapy Drugs

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.

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Evaluation of Dimer of Epicatechin from an Endophytic Fungus Curvularia australiensis FC2AP on Acute Toxicity Levels, Anti-Inflammatory and Anti-Cervical Cancer Activity in Animal Models

Molecules ◽

10.3390/molecules26030654 ◽

2021 ◽

Vol 26 (3) ◽

pp. 654

Author(s):

Vellingiri Manon Mani ◽

Arockiam Jeyasundar Parimala Gnana Soundari ◽

Balamuralikrishnan Balasubramanian ◽

Sungkwon Park ◽

Utthapon Issara ◽

...

Keyword(s):

Cervical Cancer ◽

Acute Toxicity ◽

Endophytic Fungus ◽

Lethal Dose ◽

Chemotherapeutic Agents ◽

Cancer Drug ◽

Dependent Manner ◽

Anti Cancer ◽

Albino Mice ◽

Anti Inflammatory

Cervical cancer, as the most frequent cancer in women globally and accounts almost 14% in India. It can be prevented or treated with vaccines, radiation, chemotherapy, and brachytherapy. The chemotherapeutic agents cause adverse post effects by the destruction of the neighboring normal cells or altering the properties of the cells. In order to reduce the severity of the side effects caused by the chemically synthesized therapeutic agents, the current research developed an anti-cancer agent dimer of epicatechin (DoE), a natural bioactive secondary metabolite (BSM) mediated from an endophytic fungus Curvularia australiensis FC2AP. The investigation has initiated with the evaluation of inhibiting the angiogenesis which is a main activity in metastasis, and it was assessed through Hen’s Egg Test on Chorio Allantoic Membrane (HET-CAM) test; the BSM inhibited the growth of blood vessels in the developing chick embryo. Further the DoE was evaluated for its acute toxicity levels in albino mice, whereas the survival dose was found to be 1250 mg/kg and the lethal dose was 1500 mg/kg body weight of albino mice; hematological, biochemical, and histopathological analyses were assessed. The anti-inflammatory responses of the DoE were evaluated in carrageenan induced Wistar rats and the reduction of inflammation occurred in a dose-dependent manner. By fixing the effective dose for anti-inflammation analysis, the DoE was taken for the anti-cervical cancer analysis in benzo (a) pyrene induced female Sprague-Dawley rats for 60 days trial. After the stipulated days, the rats were taken for hematological antioxidants, lipid peroxidation (LPO), member bound enzymes, cervical histopathological and carcinogenic markers analyses. The results specified that the DoE has the capability of reducing the tumor in an efficient way. This is the first report of flavonoid-DoE production from an endophytic fungus C. australiensis has the anticancer potentiality and it can be stated as anti-cancer drug.

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Probiotics for the Chemoprotective Role Against the Toxic Effect of Cancer Chemotherapy

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210514000615 ◽

2021 ◽

Vol 21 ◽

Author(s):

Aafrin Waziri ◽

Charu Bharti ◽

Mohammed Aslam ◽

Parween Jamil ◽

Aamir Mirza ◽

...

Keyword(s):

Side Effects ◽

Clinical Management ◽

Clinical Evidence ◽

Unmet Need ◽

Chemotherapeutic Agents ◽

Antitumor Effects ◽

Anti Cancer ◽

Different Types ◽

Growth Promoting ◽

High Degree

Background: The processes of chemo- and radiation therapy-based clinical management of different types of cancers are associated with toxicity and side effects of chemotherapeutic agents. So, there is always an unmet need to explore agents to reduce such risk factors. Among these, natural products have generated much attention because of their potent antioxidant and antitumor effects. In the past, some breakthrough outcomes established that various bacteria in the human intestinal gut are bearing growth-promoting attributes and suppressing the conversion of pro-carcinogens into carcinogens. Hence, probiotics integrated approaches are nowadays being explored as rationalized therapeutics in the clinical management of cancer. Methods: Here, published literature was explored to review chemoprotective roles of probiotics against toxic and side effects of chemotherapeutics. Results: Apart from excellent anti-cancer abilities, probiotics are bearing and alleviate toxicity and side effects of chemotherapeutics, with a high degree of safety and efficiency. Conclusion: Preclinical and clinical evidence suggested that due to the chemoprotective roles of probiotics against side effects and toxicity of chemotherapeutics, their integration in chemotherapy would be a judicious approach.

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Natural-Derived Molecules as a Potential Adjuvant in Chemotherapy: Normal Cell Protectors and Cancer Cell Sensitizers

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210623104227 ◽

2021 ◽

Vol 21 ◽

Author(s):

Rajib Hossain ◽

Muhammad Torequl Islam ◽

Mohammad S. Mubarak ◽

Divya Jain ◽

Rasel Khan ◽

...

Keyword(s):

Oxidative Stress ◽

Side Effects ◽

Cancer Cells ◽

Chemotherapeutic Agents ◽

Polyphenolic Compounds ◽

Anticancer Effect ◽

Anticancer Activities ◽

Normal Cells ◽

Anti Cancer ◽

Global Threat

Background: Cancer is a global threat to humans and a leading cause of death worldwide. Cancer treatment includes, among other things, the use of chemotherapeutic agents, compounds that are vital for treating and preventing cancer. However, chemotherapeutic agents produce oxidative stress along with other side effects that would affect the human body. Objective: To reduce the oxidative stress of chemotherapeutic agents in cancer and normal cells by naturally derived compounds with anti-cancer properties, and protect normal cells from the oxidation process. Therefore, the need to develop more potent chemotherapeutics with fewer side effects has become increasingly important. Method: Recent literature dealing with the antioxidant and anticancer activities of the naturally naturally-derived compounds: morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin has been surveyed and examined in this review. For this, data were gathered from different search engines, including Google Scholar, ScienceDirect, PubMed, Scopus, Web of Science, Scopus, and Scifinder, among others. Additionally, several patient offices such as WIPO, CIPO, and USPTO were consulted to obtain published articles related to these compounds. Result: Numerous plants contain flavonoids and polyphenolic compounds such as morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin, which exhibit ‎antioxidant, anti-inflammatory, and anti-carcinogenic actions via several mechanisms. These compounds show sensitizers of cancer cells and protectors of healthy cells. Moreover, these compounds can reduce oxidative stress, which is accelerated by chemotherapeutics and exhibit a potent anticancer effect on cancer cells. Conclusions: Based on these findings, more research is recommended to explore and evaluate such flavonoids and polyphenolic compounds.

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Anti-cancer palladium complexes: a focus on PdX2L2, palladacycles and related complexes

Chemical Society Reviews ◽

10.1039/c4cs00063c ◽

2014 ◽

Vol 43 (13) ◽

pp. 4751-4777 ◽

Cited By ~ 175

Author(s):

Anant R. Kapdi ◽

Ian J. S. Fairlamb

Keyword(s):

Chemotherapeutic Agents ◽

Palladium Complexes ◽

Modes Of Action ◽

Anti Cancer

Much success has been achieved with platinum-based chemotherapeutic agents,i.e.through interactions with DNA. The long-term application of Pt complexes is thwarted by issues, leading scientists to examine other metals such as palladium which could exhibit complementary modes of action.

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Secondary Metabolites from Saccharomyces cerevisiae Species with Anticancer Potential

10.5772/intechopen.95067 ◽

2021 ◽

Author(s):

Muhammad Jahangeer ◽

Areej Riasat ◽

Zahed Mahmood ◽

Muhammad Numan ◽

Naveed Munir ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Secondary Metabolites ◽

Apoptotic Cell ◽

Inhibitory Effect ◽

Chemotherapeutic Agents ◽

Chemotherapeutic Drugs ◽

Central Metabolism ◽

Biotic Stresses ◽

Micro Organisms ◽

New Chemotherapeutic Agents

Chemotherapeutic agents produce from numerous sources such as animals, plants and micro-organisms are derived from the natural products. Although the existing therapeutic pipeline lacks fungal-derived metabolites, but hundreds of secondary metabolites derived from fungi are known to be possible chemotherapies. Over the past three decades, several secondary metabolites such as flavonoids, alkaloids, phenolic and polyketides have been developed by Saccharomyces cerevisiae species with exciting activities that considered valued for the growth of new chemotherapeutic agents. Many secondary metabolites are protective compounds which prevent abiotic and biotic stresses, i.e. predation, infection, drought and ultraviolet. Though not taking part in a living cell’s central metabolism, secondary metabolites play an important role in the function of an organism. Nevertheless, due to slow biomass build-up and inadequate synthesis by the natural host the yield of secondary metabolites is low by direct isolation. A detailed comprehension of biosynthetic pathways for development of secondary metabolites are necessary for S. cerevisiae biotransformation. These metabolites have higher inhibitory effect, specificity among cancer and normal cells, and the mechanism of non-apoptotic cell killing. This study shows the significance of bioactive compounds produced by S. cerevisiae species with their possible activity and value in chemotherapeutic drugs pipeline. The isolation and alteration of these natural secondary metabolites would promote the development of chemotherapeutic drugs.

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