Voltage-activated Ca channels are expressed as multimeric proteins that allow Ca2+ ions to enter the cell. These channels are activated in response to a hormonal or chemical stimulus and membrane depolarization (Berridge, 1998). Many cells and neurons express multiple Ca2+ channel subtypes which are selectively localized to areas of the cell. The distribution of functionally unique Ca2+ channels allows for precise temporal and spatial control of intracellular calcium ([Ca]_i) and supports regulation of cellular activity in signaling. T-type Ca2+ channels are a subtype of Ca2+ channel that are expressed in a variety of cell types including some cancer cells (Perez-Reyes, 1998; Bertolesi, 2002). T-type Ca2+ channels can give rise to continuous calcium influx into the cell in a range of membrane potentials close to the resting membrane potential of cells. Alterations in T-type Ca2+ channel expression and activity has been associated with developing cycling cells with increased in expression during active growth and decreases in expression on cessation of growth and differentiation of mature cell types (Ciapa et al., 1994; Day et al., 1998; Guo et al., 1998; Kuga et al., 1996; Bertolesi et al., 2002)

Previous work in MCF-7 breast cancer cells has identified T-type Ca2+ channel subtypes and demonstrated that pharmacological block of T-channels can inhibit proliferation of MCF-7 cells and induce apoptotic cell death (Bertolesi et al., 2002), suggesting that inhibition of T-channels represent a target for drugs that can inhibit breast cancer cell growth. The precise role of T channels during cell growth, as well as their regulation, remains largely unknown at present. However, accumulated data from a variety of cell types suggests that these protein ion channels may play a fundamental role in regulating Ca2+ in proliferating cycling cells. Alterations in ion channels and Ca influx has been implicated in cancer (Yao et al., 1999) and in a human colon cancer cell line a gene encoding a T-type Ca2+ channel, was identified as having altered function (Toyota et al., 1999). These findings suggest that alterations in Ca2+ channels have the potential to affect the growth of cancer cells with inhibition of T-type Ca channels favoring growth inhibition.

Ion channels as Potential Targets in Cancer Therapy:

Voltage-gated Ca channels are major targets for a variety of therapeutic agents. A number of different drug classes, such as dihydropyridines (DHPs), benzothiazepines and phenylalkylamines, target Ca channels and are used in the treatment of hypertension, stroke, ischemia, migraine and epilepsy. To-date, however, the existence of selective T-type Ca2+ channel blockers has been rather limited with only a handful of unrelated agents exhibiting any specificity for T-type channels. One T-type channel blocking drug however, which does appear to exhibit some selectivity for T channels over other Ca2+ channels at micromolar doses is the drug, mibefradil (Mishra et al., 1994). In keeping with a role for T-type Ca channels in cell growth, studies have demonstrated that mibefradil can inhibit cellular proliferation (Schmitt et al., 1995), and in a retinoblastoma tumor cell line, mibefradil produces cytotoxicity and death of tumor cells at concentrations very closed to that required to produce T-type Ca2+ channel inhibition (IC₅₀ = <1mM) (Bertolesi et al., 2002). This study also indicated that this drug may be equally effective in killing MCF-7 breast cancer cells. The mechanisms by which mibefradil produces tumor cell death are presently unknown, although this drug has also been reported to inhibit Cl^- channels, albeit a higher concentrations, than it produces T-channel inhibition (Nilius,1997).

Cancer Growth:

Cells are formed through a process known as mitosis. A cell passes through four phases (prophase, metaphase, anaphase and telophase) where it duplicates it chromosomes and divides in two, forming two ‘daughter’ cells. Those daughter cells then divide in the same process. This type of cell growth is essential for the formation of cells such as skin and blood. A cancer cell is a mutated cell that does not respond to normal signals. It divides excessively and invades other tissues; if left unnoticed, it can kill the organism. If and when cancer cells stop dividing, they do so at what seems to be random points in their cycle. With a continued supply of nutrients, cancer cells could continue to grow indefinitely, and are said to be ‘immortal’. By contrast, normal mammalian cells divide between thirty and forty times before they stop dividing and die. Normally, the immune system is able to destroy insurgent cells, but if they escape destruction, they may grow and proliferate to form a tumor. A tumor is a mass of cancer cells within an otherwise normal tissue. If the cells remain at this site, the tumor is called benign, and can usually be removed with surgery. The tumor is called malignant when it becomes invasive and threatens or impairs the functions of other tissues and organs. Besides their lack of self control, cancer cells usually have unusual numbers of chromosomes, deranged metabolism, and cease to function in normal ways. The cells also lose their attachment to neighboring cells and can easily spread to tissues surrounding the tumor. The cancer cells often travel through the circulatory system (lymph and blood vessels) to surrounding tissues and organs. Its cause and behavior and preventative measures are being studied in depth. Recent studies have lead to the use of certain drugs to stop the proliferation of cancerous cells before they spread to other parts of the body.

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