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

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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Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence

Antioxidants ◽

10.3390/antiox9060532 ◽

2020 ◽

Vol 9 (6) ◽

pp. 532 ◽

Cited By ~ 7

Author(s):

Juhyun Shin ◽

Min-Ho Song ◽

Jae-Wook Oh ◽

Young-Soo Keum ◽

Ramesh Kumar Saini

Keyword(s):

Oxidative Stress ◽

Cancer Cells ◽

Apoptotic Cell ◽

Research Gaps ◽

Cytotoxic Effects ◽

Normal Cells ◽

Anti Cancer ◽

Antioxidant Function ◽

High Level ◽

Β Carotene

Carotenoids are well known for their potent antioxidant function in the cellular system. However, in cancer cells with an innately high level of intracellular reactive oxygen species (ROS), carotenoids may act as potent pro-oxidant molecules and trigger ROS-mediated apoptosis. In recent years, the pro-oxidant function of several common dietary carotenoids, including astaxanthin, β-carotene, fucoxanthin, and lycopene, has been investigated for their effective killing effects on various cancer cell lines. Besides, when carotenoids are delivered with ROS-inducing cytotoxic drugs (e.g., anthracyclines), they can minimize the adverse effects of these drugs on normal cells by acting as antioxidants without interfering with their cytotoxic effects on cancer cells as pro-oxidants. These dynamic actions of carotenoids can optimize oxidative stress in normal cells while enhancing oxidative stress in cancer cells. This review discusses possible mechanisms of carotenoid-triggered ROS production in cancer cells, the activation of pro-apoptotic signaling by ROS, and apoptotic cell death. Moreover, synergistic actions of carotenoids with ROS-inducing anti-cancer drugs are discussed, and research gaps are suggested.

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Ab Initio Studies of Anti-Cancer Drugs

Molecular Orbital Calculations for Biological Systems ◽

10.1093/oso/9780195098730.003.0011 ◽

1998 ◽

Author(s):

Anne-Marie Sapse

Keyword(s):

Cancer Therapy ◽

Ab Initio ◽

Cancer Cells ◽

Alkylating Agents ◽

Experimental Studies ◽

Chemotherapeutic Agents ◽

Theoretical Studies ◽

Cancer Drugs ◽

Normal Cells ◽

Anti Cancer

Cancer is an extraordinarily complicated group of diseases which are characterized by the loss of normal control of the maintenance of cellular organization in the tissues. It is still not completely understood how much of the disease is of genetic, viral, or environmental origin. The result, however, is that cancer cells possess growth advantages over normal cells, a reality which damages the host by local pressure effects, destruction of tissues, and secondary systemic effects. As such, a goal of cancer therapy is the destruction of cancer cells via chemotherapeutic agents or radiation. Since the late 1940s, when Farber treated leukemia with methotrexate, cancer therapy with cytotoxic drugs made enormous progress. Chemotherapy is usually integrated with other treatments such as surgery, radiotherapy, and immunotherapy, and it is clear that post-surgery, it is effective with solid tumors. This is due to the fact that only systemic therapy can attack micrometastases. The rationale for using chemotherapy is the control of tumor-cell populations via a killing mechanism. The major problem in this approach is the lack of selectivity of chemotherapeutic agents. Some agents indeed preferentially kill cancer cells, but no agents have been synthesized yet which kill only cancer cells and do not affect normal cells. Unfortunately, normal tissues are affected, giving rise to a multitude of side effects. In addition to drugs exhibiting cytotoxic activity, antiproliferative drugs are also formulated. According to their mode of action, anti-cancer drugs are divided into several classes. . . . alkylating agents antimetabolites DNA intercalators mitotic inhibitors lexitropsins drugs which bind covalently to DNA . . . Experimental studies of these molecules are complemented and enhanced by theoretical studies. Some of the theoretical studies use molecular mechanics methods while others apply ab initio or semi-empirical quantum-chemistry methods. Most of these molecules are large and besides their structures and properties it is important to investigate their interaction with DNA fragments (themselves large molecules). Ab initio calculations cannot always be applied to the whole system. Therefore, models are used and through a judicious choice of the entities investigated, the calculations can shed light on the problem and provide enough information to complement the experimental studies.

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Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy

Current Medicinal Chemistry ◽

10.2174/0929867325666180719145819 ◽

2020 ◽

Vol 27 (13) ◽

pp. 2118-2132 ◽

Cited By ~ 5

Author(s):

Aysegul Hanikoglu ◽

Hakan Ozben ◽

Ferhat Hanikoglu ◽

Tomris Ozben

Keyword(s):

Oxidative Stress ◽

Drug Resistance ◽

Side Effects ◽

Cancer Therapy ◽

Tumor Cells ◽

Anticancer Drugs ◽

Chemotherapeutic Agents ◽

Oxidation Reactions ◽

Hybrid Compounds ◽

Induced Apoptosis

: Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.

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Molecular Studies on Novel Antitumor Bis 1,4-Dihydropyridine Derivatives Against Lung Carcinoma and their Limited Side Effects on Normal Melanocytes

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666181019095007 ◽

2019 ◽

Vol 18 (15) ◽

pp. 2156-2168 ◽

Cited By ~ 7

Author(s):

Magda F. Mohamed ◽

Nada S. Ibrahim ◽

Ahmed H.M. Elwahy ◽

Ismail A. Abdelhamid

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Cancer Cells ◽

Cell Line ◽

Lung Carcinoma ◽

Carcinoma Cell ◽

Normal Cells ◽

Lung Carcinoma Cell Line ◽

Molecular Studies ◽

Dihydropyridine Derivatives

Background: Cancer is a complex genetic disease which is characterized by an abnormal cell growth, invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR) modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also 1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila. Objective: The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against lung cancer. Method: An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated. Results: All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds 7, 8, and 9 showed comparable IC50 values. In case of breast cancer cell line (MCF7), the most active one was compound 7, while compound 8 recorded the least activity. Conclusion: we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed the results of cell cycle assay which showed good binding energy between the compounds and the active site of enzyme indicating the inhibition of the enzyme.

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Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments

Cancers ◽

10.3390/cancers13133263 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3263

Author(s):

Alicia González ◽

Carolina Alonso-González ◽

Alicia González-González ◽

Javier Menéndez-Menéndez ◽

Samuel Cos ◽

...

Keyword(s):

Synergistic Effect ◽

Protective Effect ◽

Cancer Cells ◽

Tumor Cells ◽

Chemotherapeutic Agents ◽

Inhibitory Effects ◽

Anticancer Effect ◽

Cancer Treatments ◽

Melatonin Administration ◽

Effects Of Radiation

Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.

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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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Investigating Dermatologic Side Effects of Anti-Cancer Chemotherapeutic Agents

Journal of the Turkish Academy of Dermatology ◽

10.4274/jtad.galenos.2020.81300 ◽

2020 ◽

Vol 14 (4) ◽

pp. 102-106

Author(s):

Melis Gönülal ◽

Murat Keser ◽

Aylin Öztürk

Keyword(s):

Side Effects ◽

Chemotherapeutic Agents ◽

Anti Cancer

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Cellular Levels of Oxidative Stress Affect the Response of Cervical Cancer Cells to Chemotherapeutic Agents

BioMed Research International ◽

10.1155/2014/574659 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 23

Author(s):

Maria Filippova ◽

Valery Filippov ◽

Vonetta M. Williams ◽

Kangling Zhang ◽

Anatolii Kokoza ◽

...

Keyword(s):

Oxidative Stress ◽

Cervical Cancer ◽

Cancer Cells ◽

Adaptive Systems ◽

Chemotherapeutic Agents ◽

Rt Pcr ◽

Cellular Models ◽

Siha Cells ◽

Ros Metabolism ◽

Cervical Cancer Cells

Treatment of advanced and relapsed cervical cancer is frequently ineffective, due in large part to chemoresistance. To examine the pathways responsible, we employed the cervical carcinoma-derived SiHa and CaSki cells as cellular models of resistance and sensitivity, respectively, to treatment with chemotherapeutic agents, doxorubicin, and cisplatin. We compared the proteomic profiles of SiHa and CaSki cells and identified pathways with the potential to contribute to the differential response. We then extended these findings by comparing the expression level of genes involved in reactive oxygen species (ROS) metabolism through the use of a RT-PCR array. The analyses demonstrated that the resistant SiHa cells expressed higher levels of antioxidant enzymes. Decreasing or increasing oxidative stress led to protection or sensitization, respectively, in both cell lines, supporting the idea that cellular levels of oxidative stress affect responsiveness to treatment. Interestingly, doxorubicin and cisplatin induced different profiles of ROS, and these differences appear to contribute to the sensitivity to treatment displayed by cervical cancer cells. Overall, our findings demonstrate that cervical cancer cells display variable profiles with respect to their redox-generating and -adaptive systems, and that these different profiles have the potential to contribute to their responses to treatments with chemotherapy.

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Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation

Biochemical Journal ◽

10.1042/bj20081258 ◽

2009 ◽

Vol 418 (1) ◽

pp. 29-37 ◽

Cited By ~ 234

Author(s):

Nùkhet Aykin-Burns ◽

Iman M. Ahmad ◽

Yueming Zhu ◽

Larry W. Oberley ◽

Douglas R. Spitz

Keyword(s):

Oxidative Stress ◽

Cancer Cells ◽

Mammary Epithelial Cells ◽

Human Cancer ◽

Differential Susceptibility ◽

Glucose Deprivation ◽

Human Colon ◽

Normal Cells ◽

Ht29 Cells ◽

And Oxidative Stress

Cancer cells, relative to normal cells, demonstrate increased sensitivity to glucose-deprivation-induced cytotoxicity. To determine whether oxidative stress mediated by O2•− and hydroperoxides contributed to the differential susceptibility of human epithelial cancer cells to glucose deprivation, the oxidation of DHE (dihydroethidine; for O2•−) and CDCFH2 [5- (and 6-)carboxy-2′,7′-dichlorodihydrofluorescein diacetate; for hydroperoxides] was measured in human colon and breast cancer cells (HT29, HCT116, SW480 and MB231) and compared with that in normal human cells [FHC cells, 33Co cells and HMECs (human mammary epithelial cells)]. Cancer cells showed significant increases in DHE (2–20-fold) and CDCFH2 (1.8–10-fold) oxidation, relative to normal cells, that were more pronounced in the presence of the mitochondrial electron-transport-chain blocker, antimycin A. Furthermore, HCT116 and MB231 cells were more susceptible to glucose-deprivation-induced cytotoxicity and oxidative stress, relative to 33Co cells and HMECs. HT29 cells were also more susceptible to 2DG (2-deoxyglucose)-induced cytotoxicity, relative to FHC cells. Overexpression of manganese SOD (superoxide dismutase) and mitochondrially targeted catalase significantly protected HCT116 and MB231 cells from glucose-deprivation-induced cytotoxicity and oxidative stress and also protected HT29 cells from 2DG-induced cytotoxicity. These results show that cancer cells (relative to normal cells) demonstrate increased steady-state levels of ROS (reactive oxygen species; i.e. O2•− and H2O2) that contribute to differential susceptibility to glucose-deprivation-induced cytotoxicity and oxidative stress. These studies support the hypotheses that cancer cells increase glucose metabolism to compensate for excess metabolic production of ROS and that inhibition of glucose and hydroperoxide metabolism may provide a biochemical target for selectively enhancing cytotoxicity and oxidative stress in human cancer cells.

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