Betulinic acid (BA) is a lupane-type pentacyclic triterpene, distributed ubiquitously throughout the plant kingdom. BA and its derivatives demonstrate multiple bioactivities, particularly an antitumor effect. This review critically describes the recent research on isolation, synthesis, and derivatization of BA and its natural analogs betulin and 23-hydroxybetulinic acid. The subsequent part of the review focuses on the current knowledge of antitumor properties, combination treatments, and pharmacological mechanisms of these compounds. A 3D-QSAR analysis of 62 BA derivatives against human ovarian cancer A2780 is also included to provide information concerning the structure-cytotoxicity relationships of these compounds.

Betulinic Acid and its Derivatives as Potential Antitumor Agents

Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavageactivating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms. Recent studies have revealed that SREBPs are markedly upregulated in human cancers, providing the mechanistic link between lipid metabolism alterations and malignancies. Pharmacological or genetic inhibition of SCAP or SREBPs significantly suppresses tumor growth in various cancer models, demonstrating that SCAP/SREBPs could serve as promising metabolic targets for cancer therapy. In this review, we will summarize recent progress in our understanding of the underlying molecular mechanisms regulating SCAP/SREBPs and lipid metabolism in malignancies, discuss new findings about SREBP trafficking, which requires SCAP N-glycosylation, and introduce a newly identified microRNA-29-mediated negative feedback regulation of the SCAP/SREBP pathway. Moreover, we will review recently developed inhibitors targeting the SCAP/SREBP pathway for cancer treatment.

SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy.

Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action.

Nowadays, cancer is one of the deadliest diseases in the world, which has been estimated to cause 9.9 million deaths in 2020. Conventional treatments for cancer commonly involve mono-chemotherapy or a combination of radiotherapy and mono-chemotherapy. However, the negative side effects of these approaches have been extensively reported and have prompted the search of new therapeutic drugs. In this context, scientific community started to look for innovative sources of anticancer compounds in natural sources, including traditional plants. Currently, numerous studies have evaluated the anticancer properties of natural compounds derived from plants, both in vitro and in vivo. In pre-clinical stages, some promising compounds could be mentioned, such as the sulforaphane or different phenolic compounds. On the other hand, some phytochemicals obtained positive results in clinical stages and were further approved for cancer treatment, such as vinca alkaloids or the paclitaxel. Nevertheless, these compounds are not exempt of limitations, such as low solubility, restricted effect on their own, negative side-effects, etc. This review aims to compile the information about the current phytochemicals used for cancer treatment and also promising candidates, main action mechanisms and also reported limitations. In this sense, some strategies to face the limitations have been considered, such as nano-based formulations to improve solubility or chemical modification to reduce toxicity. In conclusion, although more research is still necessary to develop more efficient and safe phytochemical drugs, more of these compounds might be used in future cancer therapies.

https://www.mdpi.com/1424-8247/14/2/157/pdf

Status and Challenges of Plant-Anticancer Compounds in Cancer Treatment.

Ziziphus jujuba Mill. (Z. jujuba) is a traditional herb with a long history of use for nutrition and the treatment of a broad spectrum of diseases. It grows mostly in South and East Asia, as well as in Australia and Europe. Mounting evidence shows the health benefits of Z. jujuba, including anticancer, anti-inflammation, antiobesity, antioxidant, and hepato- and gastrointestinal protective properties, which are due to its bioactive compounds. Chemotherapy, such as with cis-diamminedichloroplatinium (CDDP, cisplatin) and its derivatives, is widely used in cancer treatment. It is an effective treatment for human cancers, including ovarian cancer; however, drug resistance is a major obstacle to successful treatment. A better understanding of the mechanisms and strategies for overcoming chemoresistance can greatly improve therapeutic outcomes for patients. In this review article, the bioactive compounds present in Z. jujuba are explained. The high prevalence of many different cancers worldwide has recently attracted the attention of many researchers. This is why our research group focused on studying the anticancer activity of Z. jujuba as well as its impact on chemoresistance both in vivo and in vitro. We hope that these studies can lead to a promising future for cancer patients.

"Ziziphus jujuba": A red fruit with promising anticancer activities.

Breast cancer is a major public health problem and the low effectiveness of conventional therapies to achieve long-term survival results in increased mortality associated with advanced breast cancers. Betulinic acid (BA) is a pentacyclic triterpene which can be isolated from number of plants grown in the tropics. It exhibits cytotoxic activity against variety of cancer cell lines. In the present study, the in vitro cytotoxic activity and in vivo antitumor activity of BA was evaluated in athymic nude mice bearing MCF-7 breast adenocarcinoma xenografts. In vitro cytotoxic activity of BA on MCF-7 cells was studied using the MTT assay and BA was cytotoxic towards MCF-7 cells with IC50 value of 13.5 microg/mL. The antitumor activity of BA was studied at concentrations of 50 and 100 mg/kg body weight in mice injected with MCF-7 cells. BA treatment delayed tumor formation and statistically significant reduction (P < 0.0001) of 52 and 77% in the tumor size at concentrations of 50 and 100 mg, respectively was observed. Histopathological analysis of tumors revealed decreased angiogenesis, proliferation and invasion in BA treated animals. This is one of the first studies demonstrating the in vivo antitumor activity of BA on MCF-7 breast cancer tumors in nude mice. The antitumor effect of BA can further be enhanced by use of combination therapy and novel drug delivery systems, thus making it a promising candidate for management of breast cancer patients.

http://nopr.niscair.res.in/bitstream/123456789/19386/1/IJEB%2051%287%29%20485-491.pdf

Archana A Damle

Papers

Anticancer activity of betulinic acid on MCF-7 tumors in nude mice