Targeting Ca²⁺ signalling through phytomolecules to combat cancer

Abstract

Cancer is amongst the life-threatening public health issue worldwide, hence responsible for millions of death every year. It is affecting human health regardless of their gender, age, eating habits, and ecological location. Many drugs and therapies are available for its cure still the need for effective targeted drugs and therapies are of paramount importance. In the recent past, Ca²⁺ signalling (including channels/transporters/pumps) are being studied as a plausible target for combating the cancer menace. Many evidence has shown that the intracellular Ca²⁺ homeostasis is altered in cancer cells and the remodelling is linked with tumor instigation, angiogenesis, progression, and metastasis. Focusing on these altered Ca²⁺ signalling tool kit for cancer treatment is a cross-cutting and emerging area of research. In addition, there are numerous phytomolecules which can be exploited as a potential Ca²⁺ (channels/transporters/ pumps) modulators in the context of targeting Ca²⁺ signalling in the cancer cell. In the present review, a list of plant-based potential Ca²⁺ (channel/transporters/pumps) modulators has been reported which could have application in the framework of repurposing the potential drugs to target Ca²⁺ signalling pathways in cancer cells. This review also aims to gain attention in and support for prospective research in this field.

Introduction

Globally, cancer is amongst the leading cause of death and is liable for approximately 9.6 million deaths in 2018. About 1 in 6 deaths is because of cancer, and almost one-third of deaths caused by cancer are due to common risks factors such as low fruit and vegetable intake, high body mass index, lack of physical activity, alcohol and tobacco [National Cancer Control Programme, WHO, 2002]. Additionally, anticancer drug resistance, reoccurrence of the tumor after surgery, lack of effective medication/therapy and a higher degree of side-effects are the major issues to tackle in the field of cancer research [1]. Therefore, the need for designing effective drugs for the treatment, identifying new targets and new methods for targeted drug delivery systems are never-ending. In the recent past, Ca²⁺ signalling toolkits, which are modulated in cancerous cells, are emerging as a new target to cure cancer [2]. The major causes for the deregulation of Ca²⁺ homeostasis in cancer cells are contributed by the remodelling of the particular Ca²⁺ ion transporters or pumps expression. Most of the cases depict changes in the expression of different Ca²⁺ ion channels might be specific for certain cancer sub-types. Most of the studies assessing Ca²⁺ signalling in cancer have focused on findings modulation in the expression levels of specific Ca²⁺ ion-permeable channels. During carcinogenesis, in few cancer cells, Ca²⁺ signalling is considerably modulated compromising usual physiological functions, along with enabling them to compete with normal cells by providing unlimited advantages for uncontrolled multiplication, apoptosis resistance, the formation of new blood vessels and nutrients sparse conditions, invasion and distribution away from the initial tumor site [3]. In addition to learning the receptors/pumps or channels involved in Ca²⁺ signalling that are remodelled differently at various stages of cancers such as progression, proliferation & metastasis which is still a novel area of research, there is always a constant need to explore new potential drug candidates or design new drugs candidates. Recent literature proposes that plants are a good resource to provide phytochemicals which may be useful in combating cancer by targeting modulated Ca²⁺ signalling toolkit. Several plants containing active molecules have been identified to suppress the progression and development of tumors. These phytomolecules selectively limits rapidly dividing cells, inhibit angiogenesis and induce apoptosis by targeting abnormally expressed molecular factors or cell growth factors or producing cytotoxicity in cancerous tissue [4]. For example, some flavonoids (e.g., alpinum isoflavone and methoxylicoflavanone), polyphenols (e.g., gallocatechins and resveratrol), and steroids (e.g., epibrassinolid and homocatasterone) induce apoptosis in cancer cells.

Similarly, other phytomolecules such as rutin, allicin, gingerol, β-carotene, quercetin, thymol, curcumin, and rosmarinic acid produce anticancer effects through antioxidant mechanisms. Some of them are well known to produce cytotoxicity effects, e.g., vinblastine, vincristine, elliptinium, etoposide, 10-hydroxycamptothecin, colchicinamide, curcumol, gossypol, ipomeanol, taxol, lycobetaine, tetrandrine, monocrotaline, curdione, and indirubin [5]. All such phytomolecules produce their pharmacological effects by hindering different biochemical signalling and pathways such as the LKB1-AMP kinase (AMPK) and PI3 kinase (PI3K) pathway [6]. Although, these studies do not reflect the potential of the phytomolecules in the context of cancer treatment by targeting specific Ca²⁺ ion-permeable channels/pumps, however, the opportunities of repurposing the potential of phytomolecules in targeting specific Ca²⁺ channels/pumps in cancer cells may be explored in future. In this review, an overview of Ca²⁺ signalling and how it is remodelling in cancer cell promotes the survival of cancer cells is being discussed. Additionally, various phytomolecules which have been reported to specifically blocks or regulates Ca²⁺ channels/pumps has been enlisted, in the context of their potential application to the targeted cancer cells. Furthermore, latest strategies have also been highlighted which could be applied in targeting cancer cells using plant-based molecules.