Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 21, Issue 2, 2021

Photodynamic Therapy (PDT) is a cancer therapy involving the systemic injection of a Photosensitizer (PS) that localizes to some extent in a tumor. After an appropriate time (ranging from minutes to days), the tumor is irradiated with red or near-infrared light either as a surface spot or by interstitial optical fibers. The PS is excited by the light to form a long-lived triplet state that can react with ambient oxygen to produce Reactive Oxygen Species (ROS) such as singlet oxygen and/or hydroxyl radicals, that kill tumor cells, destroy tumor blood vessels, and lead to tumor regression and necrosis. It has long been realized that in some cases, PDT can also stimulate the host immune system, leading to a systemic anti-tumor immune response that can also destroy distant metastases and guard against tumor recurrence. The present paper aims to cover some of the factors that can affect the likelihood and efficiency of this immune response. The structure of the PS, drug-light interval, rate of light delivery, mode of cancer cell death, expression of tumor-associated antigens, and combinations of PDT with various adjuvants all can play a role in stimulating the host immune system. Considering the recent revolution in tumor immunotherapy triggered by the success of checkpoint inhibitors, it appears that the time is ripe for PDT to be investigated in combination with other approaches in clinical scenarios.

Colorectal Cancer (CRC) has a high mortality rate and is one of the most difficult diseases to manage due to tumour resistance and metastasis. The treatment of choice for CRC is reliant on the phase and time of diagnosis. Despite several conventional treatments available to treat CRC (surgical excision, chemo-, radiationand immune-therapy), resistance is a major challenge, especially if it has metastasized. Additionally, these treatments often cause unwanted adverse side effects and so it remains imperative to investigate alternative combination therapies. Photodynamic Therapy (PDT) is a promising treatment modality for the primary treatment of CRC, since it is non-invasive, has few side effects and selectively damages only cancerous tissues, leaving adjacent healthy structures intact. PDT involves three fundamentals: a Photosensitizer (PS) drug localized in tumour tissues, oxygen, and light. Upon PS excitation using a specific wavelength of light, an energy transfer cascade occurs, that ultimately yields cytotoxic species, which in turn induces cell death. Cannabidiol (CBD) is a cannabinoid compound derived from the Cannabis sativa plant, which has shown to exert anticancer effects on CRC through different pathways, inducing apoptosis and so inhibiting tumour metastasis and secondary spread. This review paper highlights current conventional treatment modalities for CRC and their limitations, as well as discusses the necessitation for further investigation into unconventional active nanoparticle targeting PDT treatments for enhanced primary CRC treatment. This can be administered in combination with CBD, to prevent CRC secondary spread and enhance the synergistic efficacy of CRC treatment outcomes, with less side effects.

Cancer is among the leading causes of mortality and morbidity worldwide. Among the different types of cancers, lung cancer is considered to be the leading cause of death related to cancer and the most commonly diagnosed form of such disease. Chemotherapy remains a dominant treatment modality for many types of cancers at different stages. However, in many cases, cancer cells develop drug resistance and become nonresponsive to chemotherapy, thus, necessitating the exploration of alternative and /or complementary treatment modalities. Photodynamic Therapy (PDT) has emerged as an effective treatment modality for various malignant neoplasia and tumors. In PDT, the photochemical interaction of light, Photosensitizer (PS) and molecular oxygen produces Reactive Oxygen Species (ROS), which induces cell death. Combination therapy, by using PDT and chemotherapy, can promote synergistic effect against this fatal disease with the elimination of drug resistance, and enhancement of the efficacy of cancer eradication. In this review, we give an overview of chemotherapeutic modalities, PDT, and the different types of drugs associated with each therapy. Furthermore, we also explored the combined use of chemotherapy and PDT in the course of lung cancer treatment and how this approach could be the last resort for thousands of patients that have been diagnosed by this fatal disease.

Background: Cutaneous malignancies most commonly arise from skin epidermal cells. These cancers may rapidly progress from benign to a metastatic phase. Surgical resection represents the gold standard therapeutic treatment of non-metastatic skin cancer while chemo- and/or radiotherapy are often used against metastatic tumors. However, these therapeutic treatments are limited by the development of resistance and toxic side effects, resulting from the passive accumulation of cytotoxic drugs within healthy cells. Objective: This review aims to elucidate how the use of monoclonal Antibodies (mAbs) targeting specific Tumor Associated Antigens (TAAs) is paving the way to improved treatment. These mAbs are used as therapeutic or diagnostic carriers that can specifically deliver cytotoxic molecules, fluorophores or radiolabels to cancer cells that overexpress specific target antigens. Results: mAbs raised against TAAs are widely in use for e.g. differential diagnosis, prognosis and therapy of skin cancers. Antibody-Drug Conjugates (ADCs) particularly show remarkable potential. The safest ADCs reported to date use non-toxic photo-activatable Photosensitizers (PSs), allowing targeted Photodynamic Therapy (PDT) resulting in targeted delivery of PS into cancer cells and selective killing after light activation without harming the normal cell population. The use of near-infrared-emitting PSs enables both diagnostic and therapeutic applications upon light activation at the specific wavelengths. Conclusion: Antibody-based approaches are presenting an array of opportunities to complement and improve current methods employed for skin cancer diagnosis and treatment.

Background: This study was designed as a continuation of a complex investigation about the phytochemical composition and biological activity of chamomile, parsley, and celery extracts against A375 human melanoma and dendritic cells. Objective: The main aim was the evaluation of the antimicrobial potential of selected extracts as well as the in vitro anticancer activity against MCF7 human breast cancer cells. Methods: In order to complete the picture regarding the phytochemical composition, molecular fingerprint was sketched out by the help of FTIR spectroscopy. The activity of two enzymes (acetylcholinesterase and butyrylcholinesterase) after incubation with the three extracts was spectrophotometrically assessed. The antimicrobial potential was evaluated by disk diffusion method. The in vitro anticancer potential against MCF7 human breast cancer cells was appraised by MTT, LDH, wound healing, cell cycle, DAPI, Annexin-V-PI assays. Results: The results showed variations between the investigated extracts in terms of inhibitory activity against enzymes, such as acetyl- and butyrilcholinesterase. Chamomile and parsley extracts were active only against tested Gram-positive cocci, while all tested extracts displayed antifungal effects. Among the screened samples at the highest tested concentration, namely 60μg/mL, parsley was the most active extract in terms of reducing the viability of MCF7 - human breast adenocarcinoma cell line and inducing the release of lactate dehydrogenase. On the other hand, chamomile and celery extracts manifested potent anti-migratory effects. Furthermore, celery extract was the most active in terms of total apoptotic events, while chamomile extract induced the highest necrosis rate. Conclusion: The screened samples containing phytochemicals belonging in majority to the class of flavonoids and polyphenols can represent candidates for antimicrobial and anticancer agents.

Background and Objective: ERK pathway is one of the most crucial pathways in lung cancer metastasis. Targeting its pathway is decisive in lung cancer research. Thus, this study demonstrated for the first time for significant and selective anti-metastatic effects of lupeol against lung cancer A549 cells via perturbations in the ERK signaling pathway. Materials and Methods: Human protein targets of lupeol were predicted in silico. Migration and cytotoxicity assays were carried out in vitro. Expression levels of proteins Erk1/2 and pErk1/2 were ensured using Enzyme- Linked Immunosorbent Assay (ELISA). Semi-quantitative RT-PCR technique was used to estimate changes in crucial mesenchymal marker gene expression levels of N-cadherin and vimentin. Results: Lupeol was found to target ERK and MEK proteins effectively. Despite having no cytotoxic effects, lupeol also significantly inhibited cell migration in A549 cells with decreased expression of the pErk1/2 protein along with N-cadherin and vimentin genes. Conclusion: Lupeol inhibits cell migration, showed no cytotoxic effects on A549 cells, decreased pErk1/2 and EMT gene expression. Thus, it can serve as a potential ERK pathway inhibitor in lung cancer therapeutics.

Background: Cancer refers to a collection of diseases where cells begin to multiply uncontrollably. Breast cancer is the most predominant malignancy in women. Herbal medicine is one of the important health care systems in most developing countries. Many studies have shown that naturally occurring compounds may support the prevention and treatment of various diseases, including cancer. Some of the plant extracts and isolated compounds show photosensitizing activities and reduce cell proliferation whereas some have revealed photoprotective effects. Objectives: The biological properties and medicinal uses of extracts and bioactive compounds from V. nilgiriensis have not been investigated. This study aims to evaluate the cytotoxic effects of V. nilgiriensis in combination with 680nm laser irradiation on MCF-7 breast cancer cells. Methods: The inverted microscopy, ATP and LDH assay were used to analyze the cellular morphology, proliferation, cytotoxicity respectively after the treatment with V. nilgiriensis bark extract. The diode laser of wavelength 680nm and 15 J/cm² fluency has been used for laser irradiation. The activity of apoptotic proteins was studied using ELISA and nuclear damage by Hoechst staining. Results: The exposure of V. nilgiriensis extracts with laser irradiation at 680nm increases the cytotoxicity and decreases the proliferation of MCF-7 cells. The results of the Hoechst stain indicated nuclear damage. Our study proved that V. nilgiriensis holds a strong cytotoxic effect on breast cancer cells alone and in combination with laser irradiation by upregulating the expression of apoptotic proteins such as caspase 3, p53 and Bax. Conclusion: The results from this study showed that the bark ethyl acetate of V. nilgiriensis and in combination with laser is effective in preventing breast cancer cell proliferation in vitro. Further work is warranted to isolate the bioactive compounds from V. nilgiriensis bark extract and study the effect of compounds in the cell death induction. Due to the cytotoxic properties, V. nilgiriensis can be considered as a potent therapeutic agent for the treatment of cancer.

Drug discovery in the scope of cancer therapy has been focused on conventional agents that nonselectively induce DNA damage or selectively inhibit the activity of key oncogenic molecules without affecting their protein levels. An emerging therapeutic strategy that garnered attention in recent years is the induction of Targeted Protein Degradation (TPD) of cellular targets by hijacking the intracellular proteolysis machinery. This novel approach offers several advantages over conventional inhibitors and introduces a paradigm shift in several pharmacological aspects of drug therapy. While TPD has been found to be the major mode of action of clinically approved anticancer agents such as fulvestrant and thalidomide, recent years have witnessed systematic endeavors to expand the repertoire of proteins amenable to therapeutic ablation by TPD. Such endeavors have led to three major classes of agents that induce protein degradation, including molecular glues, Proteolysis Targeting Chimeras (PROTACs) and Hydrophobic Tag (HyT)-based degraders. Here, we briefly highlight agents in these classes and key advances made in the field with a focus on clinical translation in cancer therapy.

Intracellular protein degradation is mediated selectively by the Ubiquitin-Proteasome System (UPS) and autophagic-lysosomal system in mammalian cells. Many cellular and physiological processes, such as cell division, cell differentiation, and cellular demise, are fine-tuned via the UPS-mediated protein degradation. Notably, impairment of UPS contributes to human disorders, including cancer and neurodegeneration. The proteasome- dependent N-degron pathways mediate the degradation of proteins through their destabilizing aminoterminal residues. Recent advances unveiled that targeting N-degron proteolytic pathways can aid in sensitizing some cancer cells to chemotherapeutic agents. Furthermore, interestingly, exploiting the N-degron feature, the simplest degradation signal in mammals, and fusing it to a ligand specific for Estrogen-Related Receptor alpha (ERRa) has demonstrated its utility in ERRa knockdown, via N-terminal dependent degradation, and also its efficiency in the inhibition of growth of breast cancer cells. These recent advances uncover the therapeutic implications of targeting and exploiting N-degron proteolytic pathways to curb growth and migration of cancer cells.

Background: Doxorubicin (DOX) is one of the most common drugs used in cancer therapy, including Hepatocellular Carcinoma (HCC). Drug resistance is one of chemotherapy’s significant problems. Emerging studies have shown that microRNAs (miRNAs) could participate in regulating this mechanism. Nevertheless, the impact of miRNAs on HCC chemoresistance is still enigmatic. Objective: Investigating the role of microRNA-520c-3p (miR-520c-3p) in the enhancement of the anti-tumor effect of DOX against HepG2 cells. Methods: Expression profile for liver-related miRNAs (384 miRNAs) has been analyzed on HepG2 cells treated with DOX using qRT-PCR. miR-520c-3p, the most deregulated miRNA, was selected for combination treatment with DOX. The expression level for LEF1, CDK2, CDH1, VIM, Mcl-1 and p53 was evaluated in miR-520c-3p transfected cells. Cell viability, colony formation, wound healing as well as apoptosis assays have been demonstrated. Furthermore, Mcl-1 protein level was measured using the western blot technique. Results: The present data indicated that miR-520c-3p overexpression could render HepG2 cells chemo-sensitive to DOX through enhancing its suppressive effects on proliferation, migration, and induction of apoptosis. The suppressive effect of miR-520c-3p involved altering the expression levels of some key regulators of cell cycle, proliferation, migration and apoptosis, including LEF1, CDK2, CDH1, VIM, Mcl-1 and p53. Interestingly, Mcl-1 was found to be one of the potential targets of miR-520c-3p, and its protein expression level was down-regulated upon miR-520c-3p overexpression. Conclusion: Our data referred to the tumor suppressor function of miR-520c-3p that could modulate the chemosensitivity of HepG2 cells towards DOX treatment, providing a promising therapeutic strategy in HCC.

Background: Identification of factors to detect and improve chemotherapy-response in cancer is the main concern. microRNA-372-3p (miR-372-3p) has been demonstrated to play a crucial role in cellular proliferation, apoptosis and metastasis of various cancers including Hepatocellular Carcinoma (HCC). However, its contribution towards Doxorubicin (Dox) chemosensitivity in HCC has never been studied. Objective: This study aims to investigate the potential role of miR-372-3p in enhancing Dox effects on HCC cell line (HepG2). Additionally, the correlation between miR-372-3p and HCC patients who received Transarterial Chemoembolization (TACE) with Dox treatment has been analyzed. Methods: Different cell processes were elucidated by cell viability, colony formation, apoptosis and wound healing assays after miR-372-3p transfection in HepG2 cells Furthermore, the miR-372-3p level has been estimated in the blood of primary HCC patients treated with TACE/Dox by quantitative real-time PCR assay. Receiver Operating Curve (ROC) analysis for serum miR-372-3p was constructed for its prognostic significance. Finally, the protein level of Mcl-1, the anti-apoptotic player, has been evaluated using western blot. Results: We found a significantly higher level of miR-372-3p in the blood of the responder group of HCC patients who received TACE with Dox than of non-responders. Ectopic expression of miR-372-3p reduced cell proliferation, migration and significantly induced apoptosis in HepG2 cells which was coupled with a decrease of anti-apoptotic protein Mcl-1. Conclusion: Our study demonstrated that miR-372-3p acts as a tumor suppressor in HCC and can act as a predictor biomarker for drug response. Furthermore, the data referred for the first time its potential role in drug sensitivity that might be a therapeutic target for HCC.

Metabolic reprogramming is a significant property of various cancer cells, which most commonly arises from the Tumor Microenvironment (TME). The events of metabolic pathways include the Warburg effect, shifting in Krebs cycle metabolites, and the rate of oxidative phosphorylation, potentially providing energy and structural requirements for the development and invasiveness of cancer cells. TME and tumor metabolism shifting have a close relationship through bidirectional signaling pathways between stromal and tumor cells. Cancer- Associated Fibroblasts (CAFs), as the most dominant cells of TME, play a crucial role in the aberrant metabolism of cancer. Furthermore, the stated relationship can affect survival, progression, and metastasis in cancer development. Recently, exosomes are considered one of the most prominent factors in cellular communications considering effective content and bidirectional mediatory effect between tumor and stromal cells. In this regard, CAF-Derived Exosomes (CDE) exhibit an efficient obligation to induce metabolic reprogramming for promoting growth and metastasis of cancer cells. The understanding of cancer metabolism, including factors related to TME, could lead to the discovery of a potential biomarker for diagnostic and therapeutic approaches in cancer management. This review focuses on the association between metabolic reprogramming and engaged microenvironmental, factors such as CAFs, and the associated derived exosomes.

Background: The use of medicinal plants for general wellbeing and disease treatment is a common practice among tribal communities of Kokrajhar districts of Assam. However, little works have been done to study the pharmacological aspect of the plants. Objectives: The present study intends to study the antioxidant and antiproliferative properties of selected medicinal plants used by the tribal communities of the Kokrajhar district of Assam since ancient times. Methods: Five traditionally important medicinal plants, namely, Cassia fistula, Citrus grandis, Lindernia crustacea, Sacciolepis myosuroides, and Zingiber zerumbet were investigated for antioxidant, antiproliferative (cytotoxic) and apoptosis-inducing potential in the malignant cancer cell line. Phytochemical content, such as phenolic and flavonoid content, were estimated following standard protocol. The methanolic extract of plants was investigated following the phosphomolybdate method (TAC), FRAP, DPPH, ABTS, and TBARS assays. Antiproliferative activities of the plants were carried out by MTT assay in DL and PBMC cells. The apoptotic study was carried out following the acridine orange and ethidium bromide staining method and fluorescent microscopic imaging. Based on the significant (P≤0.05) high apoptotic inducing potential of the plant and to further dissect the molecular mode of action, including downstream biological action, major phytochemicals derived from L. crustacea were investigated for its prospective binding affinity with anti-apoptotic cancer target proteins. Results: Antioxidant studies by FRAP, DPPH, ABTS, and TBARS assay revealed that all five plants contain considerable free radical scavenging activity. C. fistula showed the strongest free radical scavenging activity while the fruit peel extract of C. grandis showed poor activity. The overall antioxidant activities of plants such as TAC, FRAP, DPPH, ABTS, and TBARS may be arranged in decreasing activity as C. fistula > Z. zerumbet > L. crustacea > S. myosuroides > C. grandis. MTT based cell proliferation study showed that all the plants extract significantly (P≤0.05) inhibited cell viability with negligible cytotoxicity (~5-12%) in normal cells. Moreover, L. crustacea showed promising antiproliferative and apoptosis-inducing ability against Dalton’s lymphoma. It is worth mentioning that the major bioactive compounds of the most potent plant extract, L. crustacea interacted with anti-apoptotic proteins (cancer target) with higher affinity and the results are compared with reference inhibitors. Conclusion: It is worth noting that these plants have the potential to consider for further scientific studies in different cell lines and animal models. Furthermore, isolation and characterization of bioactive compound(s) may promise the discovery of new and valuable drugs candidate to tackle various human diseases.

Background: Oxaliplatin (L-OHP)-based chemotherapy, such as FOLFOX4 (5-fluorouracil, leucovorin, and L-OHP), improves the prognosis of patients with late-stage Hepatocellular Carcinoma (HCC). However, the development of resistance to L-OHP leads to the failure of chemotherapy. The aim of this study was to investigate the role of linc01559 and miR-6783-3p in regulating resistance to L-OHP. Methods: Quantitative reverse transcription-polymerase chain reaction was used to determine the expression profile. The Cell Counting Kit-8 test and wound healing assay were also used. Dual-luciferase reporter gene assay, RNA pull-down assay, and RNA immunoprecipitation were used to evaluate the interaction between linc01559 and miR-6783-3p. Result: linc01559 expression was associated with response to FOLFOX4, as well as miR-1343-3p and miR- 6783-3p expression in vivo. A nomogram, including linc01559 and miR-1343-3p, precisely and accurately predicted the overall survival of patients with HCC. Regarding the in vitro tests, linc01559 showed higher expression in L-OHP-resistant cell lines, whereas miR-6783-3p was downregulated. Knockdown of linc01559 led to decreased proliferation and migration ability, and increased expression of miR-6783-3p; however, it did not influence the expression of miR-1343-3p. We also found that linc01559 directly interacted with miR-6783-3p. Furthermore, linc01559 and miR-6783-3p regulated the viability of L-OHP-resistant cells following treatment with L-OHP. Conclusion: linc01559 promoted the proliferation of HCC by sponging miR-6783-3p. This suggests that linc01559/miR-6783-3p may be key factors in regulating resistance and response to L-OHP. Moreover, they may be potential therapeutic targets for improving sensitivity to L-OHP in patients with HCC.